EVIDENCE BASED

COVID-19: Global Overview of COVID-19 in End-Stage Kidney Disease

FIGURE 1  |  The incidence of COVID-19 and associated clinical outcomes in ESKD populations3

Table depicting the incidence of COVID-19 and associated clinical outcomes in ESKD populations, broken down by country.

Individuals on dialysis have also been observed to experience shorter duration from symptom onset to intensive care unit admission than other groups.11 A higher percentage of dialysis Individuals on dialysis have also been observed to experience shorter duration from symptom onset to intensive care unit admission than other groups.11 A higher percentage of dialysis patients (25%) also showed symptoms of altered mental status versus non-dialysis-dependent patients with CKD (12%).12 Critically ill SARS-CoV-2–positive dialysis patients had a higher likelihood of developing thromboembolic complications than those without COVID-19. These individuals also had a higher probability of requiring mechanical ventilation or extracorporeal life support.13,14

Some individuals on dialysis may not fully recover from COVID-19 and suffer from fatigue and neurologic, cardiac, gastrointestinal, and respiratory symptoms.15 Contributing factors to this “long-hauler” phenomenon in the general population—including age, female sex, obesity, asthma, neurologic deficits, and persistent inflammation—may also apply in ESKD.16 The incidence of long-haul for individuals with ESKD is not known.

DIAGNOSTIC TESTING

Common methods for detecting SARS-CoV-2 in infected individuals include RT-PCR and serological tests that primarily recognize the spike (S) protein.17,18,19,20 Sampling typically occurs by saliva, nasopharyngeal, or nasal swabs from the respiratory track for RT-PCR, or blood for antibody or serology testing.21 Many individuals infected with COVID-19, including those on dialysis, have positive RT-PCR tests that persist for weeks after recovery. However, it is not known if these individuals are more immunocompromised/immunosuppressed than the general population, or whether prolonged RT-PCR positivity is indicative of delayed clearing of infectious virions.22 It has been proposed that ESKD patients, with typically altered immune responses, could harbor live virus longer. Such prolonged SARS-CoV-2 positivity could obscure cases of still-active virus and reinfection, impacting treatment options, clinical care, duration of hospital stay, discharge planning, and hospital capacity.23,24,25

Seroconversion typically occurs between 7 and 11 days from exposure and can persist after recovery.26 A UK study found detectable immunoglobulin G (IgG) in 100% of COVID-19-positive HD patients after seven months.27 In contrast, 26% of critically ill ESKD patients could not elicit antibody responses, indicating that HD patients may be immunocompromised.28,29 Despite limitations, serological testing in ESKD may be a valuable tool to determine seroprevalence, monitor exposure, and guide improvements for infection prevention and control.

To better understand duration of seropositivity and acquired immunity, combined testing for the S and nucleocapsid proteins is currently being developed and tested in vitro.30 This approach allows for differentiation between vaccinated and infected individuals. High-quality, quantitative methodologies that evaluate persistent positivity post-infection, reinfection, potential antibody titer reduction over time, and effect of variants in ESKD patients are needed.

COVID-19 TREATMENT OPTIONS AND CHALLENGES IN ESKD

As of July 2021, COVID-19 therapeutic options for individuals living with ESKD are still limited as clinical trials often excluded this population.31,32,33,34,35,36,37 

Several monoclonal antibody (mAb) therapies were granted EUA by various global authorities. Bamlanivimab plus etesevimab, casirivimab plus imdevimab, or sotrovimab, as single or combination therapy, are recommended for non-hospitalized or mild-to-moderate COVID-19.44 No dose adjustments are needed in patients with mild-moderate renal impairment. The recombinant anti-IL-6 receptor antibody, tocilizumab, was also granted EUA in the US and was successfully used to treat non-critical hemodialysis patients with COVID-19-related pneumonia or cytokine release syndrome; no dose adjustment was needed in these patients.45 EUA status (US) for hospitalized COVID-19 patients with high convalescent plasma titers early in disease course has been given. Antiviral agents, including remdesivir, are not approved or recommended in ESKD.46,47,48

Remdesivir evaluation in ESKD has been inadequate, and it is not recommended in individuals with eGFR <30 mL/min/1.73 m2.38,39 A case series of hospitalized COVID-19-positive HD patients suggests good tolerance of standard doses of remdesivir resulting in a 52.2% discharge rate.40 In another study, administration within 48 hours of hospital admission shortened the duration of stay for dialysis patients by 5.5 days.41 Remdesivir was not significantly associated with early treatment termination due to abnormal liver function tests in patients with creatinine clearances <30 ml/min versus ≥30 ml/min., and in a separate study, plasma concentrations were 45 to 49% lower post-dialysis as compared to pre-dialysis.42,43

Worldwide, COVID-19 vaccine campaigns have focused on those at highest risk for severe disease, and a number of countries have prioritized vaccination of individuals with kidney disease. Early reports found vaccine-derived antibody responses in 96% of dialysis patients, but IgG levels were lower than controls (median: 2900 mg/L versus 7401 mg/L).49 Although more data is needed, and reported vaccine hesitancy among dialysis patients ranges from 20% to 51%, global authorities consider COVID-19 vaccines safe for individuals with ESKD and believe differences in side effects compared with the general population should be insignificant.50,51

LOOKING AHEAD

As the COVID-19 pandemic continues to evolve, there are several gaps in knowledge regarding the dialysis population that need to be addressed, as these patients have been excluded from major trials. Future research should focus on how often dialysis patients should be tested and whether the currently available tests are optimal for this population. Data is also needed on whether antibodies produced in recovered individuals with ESKD are as effective as in the general population. Research into “long COVID” in ESKD should be a priority. Transitioning more patients to home therapies now and post-COVID-19 should also be explored.

Vaccine safety and efficacy in this population are also not well understood. Results from the prospective, multicenter RECOVAC-IR study (ClinicalTrials.gov NCT04741386)—which aims to evaluate immunogenicity, safety, and antibody longevity in CKD, ESKD, and transplant patients up to 12 months post-vaccination with Moderna’s mRNA-1273 vaccine—are eagerly awaited.52 ESKD patients are immunocompromised and exhibit reduced or insufficient vaccine responses compared to healthy individuals, and strategies to overcome such impaired responses—e.g., appropriately timed booster shots or a mix of different COVID-19 vaccines—need to be determined. Whether vaccine-induced antibody formation reflects antiviral immunity in these patients is also not clear.53 For instance, absence of seroconversion may not reliably indicate a lack of protection from severe COVID-19. Cellular immunity may still be present and aff ord some protection against infection or severe disease. Importantly, the benefits of vaccination outweigh the potential risks. However, discussion on the safety profiles of approved vaccines in these patients is essential to reducing vaccine hesitancy, improving vaccine penetration, and controlling the pandemic.

 

Meet The Experts

 

Faith Kircelli, MD
Vice President, Medical Information and Education, Fresenius Medical Care Europe/Middle East/Africa

Dixie-Ann Sawin, Ms, PhD
Senior Director, Medical Information and Communication, Global Medical Office

References

  1. COVID-19 Dashboard. Johns Hopkins Coronavirus Resource Center. https://coronavirus.jhu.edu/map.html. Accessed April 12, 2021.
  2. World Covid-19 tracker: Latest cases and deaths by country. https://www.cnn.com/interactive/2020/health/coronavirus-maps-and-cases/. Accessed June 5, 2021.
  3. Information for this figure was gathered from the following sources: (UAE) Ahmed W, Al Obaidli AAK, Joseph P, et al., Outcomes of patients with end stage kidney disease on dialysis with COVID-19 in Abu Dhabi, United Arab Emirates—from PCR to antibody, BMC Nephrol 2021;22(1):198. (France) Couchoud C, Bayer F, Ayav C, et al., Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients, Kidney Int 2020;98(6). (UK) Hendra H, Vajgel G, Antonelou M, et al., Identifying prognostic risk factors for poor outcome following COVID-19 disease among in-centre haemodialysis patients: role of inflammation and frailty, J Nephrol 2021;34(2):315-23. (Europe) Jager KJ, Kramer A, Chesnaye NC, et al., Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe, Kidney Int 2020;98(6):1540-48. (China, 1st entry) Min Y, Cheng L, Tu C, et al., Clinical characteristics of deceased hemodialysis patients affected by COVID-19, Int Urol Nephrol 2021;53(4):797-802. (China, 2nd entry) Xiong F, Tang H, Liu L, et al., Clinical characteristics of and medical interventions for COVID-19 in hemodialysis patients in Wuhan, China, J Am Soc Nephrol 2020;31(7):1387-97. (Germany) Seidel M, Hölzer B, Appel H, et al., Impact of renal disease and comorbidities on mortality in hemodialysis patients with COVID-19: a multicenter experience from Germany. J Nephrol 2020;33(5). (Canada) Taji L, Thomas D, Oliver MJ, et al., Covid-19 in patients undergoing long-term dialysis in Ontario, CMAJ 2021;193(8):E278-84. (USA) Anand S, Montez-Rath M, Han J, et al., Estimated SARS-CoV-2 seroprevalence in US patients receiving dialysis 1 year after the beginning of the COVID-19 pandemic, JAMA Netw Open 2021;4(7):e2116572; and Hsu CM, Weiner DE, Aweh G, et al., COVID-19 among US dialysis patients: risk factors and outcomes from a national dialysis provider, Am J Kidney Dis 2021;77(5):748-56.e1. 
  4. Clarke C, Prendecki M, Dhutia A, et al. High prevalence of asymptomatic COVID-19 infection in hemodialysis patients detected using serologic screening. J Am Soc Nephrol 2020;31(9):1969-75. doi:10.1681/ASN.2020060827.
  5. Cummings MJ, Baldwin MR, Abrams D, et al. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. medRxiv Prepr Serv Heal Sci April 2020. doi:10.1101/2020.04.15.2006715 7.
  6. Liu J, Zhang S, Wu Z, et al. Clinical outcomes of COVID-19 in Wuhan, China: a large cohort study. Ann Intensive Care 2020;10(1). doi:10.1186/s13613-020-00706-3.
  7. Aghagoli G, Gallo Marin B, Katchur NJ, et al. Neurological involvement in COVID-19 and potential mechanisms: a review. Neurocrit Care 2020. doi:10.1007/s12028-020-01049-4.
  8. Navarrete JE, Tong DC, Cobb J, et al. Epidemiology of COVID-19 infection in hospitalized end-stage kidney disease patients in a predominantly African-American population. Am J Nephrol 2021;52(3):190-98. doi:10.1159/000514752.
  9. Smolander J, Bruchfeld A. The COVID-19 epidemic: management and outcomes of hemodialysis and peritoneal dialysis patients in Stockholm, Sweden. Kidney Blood Press Res 2021;46(2). doi:10.1159/000514268.
  10. Kang SH, Kim SW, Kim AY, et al. Association between chronic kidney disease or acute kidney injury and clinical outcomes in COVID-19 patients. J Korean Med Sci 2020;35(50). doi:10.3346/jkms.2020.35.e434.
  11. Flythe JE, Assimon MM, Tugman MJ, et al. Characteristics and outcomes of individuals with pre-existing kidney disease and COVID-19 admitted to intensive care units in the United States. Am J Kidney Dis 2021;77(2):190-203.e1. doi:10.1053/j. ajkd.2020.09.003.
  12. Ibid.
  13. Navarrete et al. Epidemiology of COVID-19 infection in hospitalized end-stage kidney disease patients.
  14. Turgutalp K, Ozturk S, Arici M, et al. Determinants of mortality in a large group of hemodialysis patients hospitalized for COVID-19. BMC Nephrol 2021;22(1):1-10. doi:10.1186/s12882-021-02233-0.
  15. Kliger AS, Silberzweig J. COVID-19 and dialysis patients: unsolved problems in early 2021. J Am Soc Nephrol 2021;32(5):1018-20. doi:10.1681/asn.2020121766.
  16. Leviner S. Recognizing the clinical sequelae of COVID-19 in adults: COVID-19 long-haulers. J Nurse Pract May 2021. doi:10.1016/j.nurpra.2021.05.003.
  17. Weissleder R, Lee H, Ko J, Pittet MJ. COVID-19 diagnostics in context. Sci Transl Med 2020;12(546). doi:10.1126/scitranslmed.abc1931.
  18. Cheng MP, Papenburg J, Desjardins M, et al. Diagnostic testing for severe acute respiratory syndrome-related coronavirus 2: a narrative review. Ann Intern Med 2020;172(11):726-34. doi:10.7326/M20-1301.
  19. Caliendo AM, Hanson, KE. COVID-19: diagnosis. UpToDate. Last updated April 16, 2021. https://www.uptodate.com/contents/covid-19-diagnosis?search=undefined&s ource=covid19_landing&usage_type=main_section#H2358377675. 
  20. World Health Organization. COVID-19 clinical management: living guidance. January 25, 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1. 
  21. Chilamakuri R, Agarwal S. COVID-19: characteristics and therapeutics. Cells 2021;10(2). doi:10.3390/cells10020206.
  22. O’Sullivan ED, Lees JS, Howie KL, et al. Prolonged SARS-CoV-2 viral shedding in patients with chronic kidney disease. Nephrology 2021;26(4):328-32. doi:10.1111/nep.13844.
  23. Ibid.
  24. Nicholson EG, Avadhanula V, Fragoso S, et al. SARS-CoV-2 re-infection versus prolonged shedding: a case series. Influenza Other Respi Viruses June 2021:irv.12879. doi:10.1111/irv.12879.
  25. Rodríguez-Grande C, Adán-Jiménez J, Catalán P, et al. Inference of active viral replication in cases with sustained positive reverse transcription-PCR results for SARS-CoV-2. J Clin Microbiol 2021;59(2). doi:10.1128/JCM.02277-20.
  26. Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect 2020;9(1):386-89. doi:10.1080/22221751.2020.1729071.
  27. Wickens O, Chinnadurai R, Mannan F, et al. Investigating the utility of COVID-19 antibody testing in end-stage renal disease patients receiving haemodialysis: a cohort study in the United Kingdom. BMC Nephrol 2021;22(1):154. doi:10.1186/s12882-021-02366-2.
  28. Ahmed W, Al Obaidli AAK, Joseph P, et al. Outcomes of patients with end stage kidney disease on dialysis with COVID-19 in Abu Dhabi, United Arab Emirates; from PCR to antibody. BMC Nephrol 2021;22(1):198. doi:10.1186/s12882-021-02378-y.
  29. Sakhi H, Dahmane D, Attias P, et al. Kinetics of anti–SARS-CoV-2 IgG antibodies in hemodialysis patients six months after infection. J Am Soc Nephrol 2021;32(5):1033-36. doi:10.1681/asn.2020111618.
  30. Klausberger M, Duerkop M, Haslacher H, et al. A comprehensive antigen production and characterisation study for easy-to-implement, specific and quantitative SARS-CoV-2 serotests. EBioMedicine 2021;67:103348. doi:10.1016/j. ebiom.2021.103348.
  31. Kliger, Silberzweig. COVID-19 and dialysis patients: unsolved problems in early 2021.
  32. Kusztal M, Myślak M. Therapeutic dilemmas in dialysis patients hospitalized for COVID-19: balancing between nihilism, off-label treatment and side effects. Clin Kidney J 2021;14(4):1039-41. doi:10.1093/ckj/sfaa274.
  33. US Food and Drug Administration. FDA combating COVID-19 with therapeutics. Last updated December 2, 2020. https://www.fda.gov/media/136832/download. 
  34. European Medicines Agency. COVID-19 treatments. https://www.ema.europa. eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines/covid-19-treatments. Accessed June 7, 2021.
  35. Mahase E. Covid-19: UK launches antivirals taskforce to deliver home treatments by autumn. BMJ 2021 Apr 26;373:n1077. doi:10.1136/bmj.n1077.
  36. Fan L, Jiang S, Yang X, et al. COVID-19 drug treatment in China. Curr Pharmacol Reports 2020;6(4):146-154. doi:10.1007/s40495-020-00218-5.
  37. Japan health ministry panel OKs 3rd COVID-19 treatment drug. Kyodo News, April 21, 2021. https://english.kyodonews.net/news/2021/04/ddf7a9194af5-japan-health-ministry-panel-oks-3rd-covid-19-treatment-drug.html.
  38. FDA combating COVID-19 with therapeutics. https://www.fda.gov/media/136832/download.
  39. FDA. MedWatch: The FDA safety information and adverse event reporting program. www.fda.gov/medwatch. Accessed July 28, 2021.
  40. Thakare S, Gandhi C, Modi T, et al. Safety of remdesivir in patients with acute kidney injury or CKD. Kidney Int Reports 2021;6(1):206-10. doi:10.1016/j. ekir.2020.10.005.
  41. Aiswarya D, Arumugam V, Dineshkumar T, et al. Use of remdesivir in patients with COVID-19 on hemodialysis: a study of safety and tolerance. Kidney Int Reports 2021;6(3):586-93. doi:10.1016/j.ekir.2020.12.003.
  42. Ackley TW, McManus D, Topal JE, et al. A valid warning or clinical lore: an evaluation of safety outcomes of remdesivir in patients with impaired renal function from a multicenter matched cohort. Antimicrob Agents Chemother 2021;65(2). doi:10.1128/AAC.02290-20.
  43. Davis MR, Pham CU, Cies JJ. Remdesivir and GS-441524 plasma concentrations in patients with end-stage renal disease on haemodialysis. J Antimicrob Chemother 2021;76(3):822-25. doi:10.1093/jac/dkaa472.
  44. Taylor PC, Adams AC, Hufford MM, et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol 2021;21(6):382-93. doi:10.1038/s41577-021- 00542-x.
  45. Castellano G, Infante B, Mercuri S, et al. Treatment of COVID-19 atypical pneumonia by early Tocilizumab administration in “non-critically-ill” patients on hemodialysis. J Nephrol 2021;34(1):259-62. doi:10.1007/s40620-020-00872-4.
  46. Ibid.
  47. Stephen S, Park YA, Chrysostomou A. Clinical benefits of Tocilizumab in COVID-19-related cytokine release syndrome in a patient with end-stage kidney disease on haemodialysis in Australia. Nephrology (Carlton) 2020;25(11):845-49. doi:10.1111/nep.13767.
  48. Mahajan R, Lipton M, Broglie L, et al. Eculizumab treatment for renal failure in a pediatric patient with COVID-19. J Nephrol  2020;33(6):1373-76. doi:10.1007/s40620-020-00858-2. 
  49. Grupper A, Sharon N, Finn T, et al. Humoral response to the Pfizer BNT162b2 vaccine in patients undergoing maintenance hemodialysis. Clin J Am Soc Nephrol April 2021:CJN.03500321. doi:10.2215/cjn.03500321.
  50. Garcia P, Montez-Rath ME, Moore H, et al. SARS-CoV-2 vaccine acceptability in patients on hemodialysis: a nationwide survey. J Am Soc Nephrol April 2021:ASN.2021010104. doi:10.1681/asn.2021010104.
  51. Rungkitwattanakul D, Yabusaki A, Singh D, et al. COVID-19 vaccine hesitancy among African American hemodialysis patients: a single-center experience. Hemodial Int 2021. doi:10.1111/hdi.12922.
  52. Kho MML, Reinders MEJ, Baan CC, et al. The RECOVAC IR study: the immune response and safety of the mRNA-1273 COVID-19 vaccine in patients with chronic kidney disease, on dialysis, or living with a kidney transplant—a prospective, controlled, multicenter observational cohort by the REnal patients COVID-19 VACcination (RECOVAC) consortium. Nephrol Dial Transplant 2021;gfab186. doi:10.1093/ndt/gfab186.
  53. Kronbichler A, Anders HJ, Fernandez-Juárez GM, et al. Recommendations for the use of COVID-19 vaccines in patients with immune-mediated kidney diseases. Nephrol Dial Transplant 2021;gfab064. doi:10.1093/ndt/gfab064.