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

Global COVID-19 data confirms that dialysis patients experienced a much higher rate of hospitalization and death than the general population. However, there has been insufficient research into many issues surrounding the immediate risks and long-term impact of COVID-19 on individuals with end stage kidney disease (ESKD). This has created a knowledge gap on many topics, including testing, vaccine efficacy, therapeutic options, prolonged positivity rates, reinfection, and the incidence and severity of “long-hauler” symptoms.

Identification of a novel ß-coronavirus in Wuhan, China, in December 2019 marked the beginning of the global COVID-19 pandemic. As of June 5, 2021, SARS-CoV-2 has infected approximately 173 million people, resulting in over 3.7 million deaths in 220 countries and territories.1,2 The COVID-19 pandemic fostered greater global collaboration in science, allowing robust COVID-19 research and almost 142,000 peer-reviewed publications indexed on PubMed.gov (by June 5, 2021). However, COVID-19 data on individuals with ESKD has been slow to emerge, with only 511 publications identified (as of June 6, 2021) that discuss topics such as epidemiology, clinical outcomes, diagnosis, testing, disease management, and therapeutic options for this high-risk population.

EPIDEMIOLOGY AND CLINICAL OUTCOMES IN ESKD

The incidence of COVID-19 in individuals with ESKD on maintenance dialysis has varied between countries (Figure 1). The noted differences are likely due to numerous factors, including: the time frame of observation and associated population rates of COVID-19, the method of identifying and ascertaining COVID-19, and differences in patient comorbidities and age.

In a cohort of 365 hemodialysis (HD) patients, 22.2 percent were symptomatic and were tested by reverse transcriptase polymerase chain reaction (RT-PCR); 36.2 percent were seropositive.4 Of the seropositive individuals on dialysis, 40.3 percent (52 out of 129) were found to be asymptomatic or undiagnosed. Thus, undiagnosed asymptomatic disease in dialysis patients can be high and may serve as an additional source of infection within the clinics. In the general population, at least 20 percent of SARS-CoV-2–infected patients experienced severe or critical illness with respiratory failure, septic shock, multiorgan failure, or neurological issues.5,6,7 Among individuals with ESKD on maintenance dialysis, rates of hospitalization associated with COVID-19 have been high and generally exceed 50 percent; mortality ranges from 10 percent to 30 percent depending on the study (Figure 1). The notable variability is presumably due to a number of factors, including the inclusion of individuals with asymptomatic and more mild disease. Comparatively, the risk for severe infection and hospitalization has been estimated to be two- to seven-fold higher for individuals with ESKD.8,9,10

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

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 percent) also showed symptoms of altered mental status versus non-dialysis-dependent patients with CKD (12 percent).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 percent of COVID-19-positive HD patients after seven months.27 In contrast, 26 percent 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 HD 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 percent 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 percent 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 percent 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 percent to 51 percent, 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 afford 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

References

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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. 
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12. Ibid.
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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.
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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.
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