COVID‑19 in patients requiring renal replacement therapy: an overview of current data and future challenges

Abstract

Patients with chronic kidney disease, especially those on renal replacement therapy, demonstrate increased incidence and mortality from COVID-19, as compared with the general population. One of the main reasons for this phenomenon is a dysfunction of the immune system associated with its accelerated aging, weakened immune functions, impaired regulation of proinflammatory reactions, chronic inflammation, and immunosuppressive therapy. Most of these patients have a high rate of comorbidities, which may also have a negative impact on the severity of COVID-19 and prognosis. Introduction of COVID-19 vaccines has significantly changed the course of the fight against the pandemic. Due to the very severe disease, in many countries the patients receiving renal replacement therapy were prioritized for vaccination right after health care professionals. Differences in the response to vaccination were noted, which required an individualized approach and modification of the vaccination program in this patient group. Difficulties in assessing these issues are due to the differences in the research methodology used in the available studies and their observational nature. Moreover, response to vaccination varied over time depending on the geographic region and variant of the virus causing the infection. The epidemiology was significantly influenced by the improved prevention methods and treatment of infections as well as the growing percentage of vaccinated and convalescent people. We present the most important differences in the epidemiology of COVID-19, the course of the disease, prognosis, and prevention, as well as the challenges associated with improving the prognosis in patients receiving renal replacement therapy.

Introduction

Since the outbreak of the COVID-19 pandemic in Wuhan in December 2019, numerous reports have been published that unequivocally demonstrate an increased incidence and mortality from COVID-19 among renal replacement patients with chronic kidney disease (CKD), that is, those on chronic hemodialysis (HD) and kidney transplant recipients (KTRs).¹ Studies from various countries have shown that this population is characterized by a very severe course of COVID-19, ending in death in almost every third patient.² This led to a situation where, in many dialysis centers, the percentage of patients who died during the pandemic was several times higher than in the corresponding period before the pandemic.^3-5 As a consequence, HD patients and immunocompromised individuals after organ transplantation were preferentially vaccinated against COVID-19 in many countries, right after health care professionals. The current review presents the most important differences among patients treated with renal replacement therapy in terms of the epidemiology of COVID-19, the course of the disease, prognosis and prevention, as well as the challenges associated with improving the prognosis in this group of patients on the eve of subsequent pandemic waves.

Different characteristics of patients

In patients with CKD, particularly those requiring renal replacement therapy, dysfunction of the immune system is found, consisting in its accelerated aging, weakening of the humoral and cellular immune functions, impaired regulation of proinflammatory reactions, and chronic inflammation.⁶ Most of such patients are elderly people with a high rate of comorbidities, including diabetes. In KTRs, a significant improvement in the functioning of the immune system is observed after transplantation, along with the return of the excretory and secretory functions of the kidneys. However, the risk of infection remains high as a result of the immunosuppressive treatment used in this population. The risk is particularly high in the first year after transplantation, when the patients take the highest doses of immunosuppressive drugs.⁷

In the case of patients treated with repeated HD procedures in a dialysis unit, there is an additional risk of developing infectious diseases, which results from numerous personal interactions related to long-term stay at the dialysis unit 3 times a week and joint transportation with other patients to and from the unit.⁸ It was not possible to limit interpersonal contacts in this group of patients during the pandemic, which was commonly done in the general population. As a consequence, the patients undergoing renal replacement therapy were more predisposed to infection with SARS-CoV-2 and to severe COVID-19.

Higher incidence

Population studies from Flanders and Poland conducted at the beginning of the pandemic^9,10 showed an approximately 4-fold higher incidence of COVID-19 among HD patients treated in a dialysis unit than in the general population, regardless of the demographic factors, socioeconomic situation, and comorbidities. It should be remembered, however, that the reported data concerned only symptomatic cases of the disease and a large proportion of patients who got infected but did not present symptoms may have been omitted. British studies show that the percentage of such asymptomatic patients may reach as much as 18.7% of all HD patients treated in dialysis centers.¹¹ On the other hand, however, the high incidence rates among HD patients could have been influenced by more frequent testing for SARS-CoV-2 infection in this group than among the general population.

The probability of SARS-CoV-2 infection was higher among Black and Hispanic individuals or those with undisclosed ethnicity, as well as among people living in predominantly Black and Hispanic neighborhoods, and it correlated with poverty and population density.¹² In addition to the factors indicated above, the high incidence rates at the beginning of the pandemic were also influenced by the limited possibilities of preventing transmission of infection due to the lack of knowledge about the principles of infection control in dialysis centers or the lack of acquired immunity following vaccination or earlier illness. The reported incidence rates in individual studies were also influenced by differences in health policies in a given country or region (eg, lockdown or no lockdown), virulence of the virus variant dominating in a given area, as well as the availability and type of vaccines. The differences were also due to the varying degree of compliance with the rules of SARS-CoV-2 infection prevention in a dialysis unit, as indicated in our previous publication.⁸ There is no doubt that patients on peritoneal dialysis (PD), who were able to significantly limit interpersonal contacts, contracted the disease less frequently. Therefore, some authors conclude that PD should be the renal replacement therapy of choice in the periods of a pandemic, regardless of the pathogen causing it.¹³

Among KTRs, the incidence of COVID-19 was higher than in the general population, but lower than in HD patients, which may be due to their more strict self-isolation and a more restrictive approach to infection prevention methods.^14,15 However, the results of the studies on KTRs also need to be approached with caution. Analyses performed early during the pandemic may have underestimated the incidence of COVID-19 in this group of patients due to limited testing of individuals with mild or asymptomatic disease, and thus paradoxically overestimated the COVID-19 mortality rate. A study showed that COVID-19 mortality rates among the KTRs dropped from 32% to 15% after taking into account cases of asymptomatic infection.¹⁶ In addition, it should be noted that some of the published epidemiological incidence data are based on the results of serological tests. In the case of KTRs, these results may therefore be underestimated, as the immunosuppressive treatment they receive contributes to a lower rate of postinfection antibody seroconversion, lower titers, and faster disappearance of antibodies than in the general population. For example, a study from New York showed that 20.3% of transplant recipients in whom infection was confirmed by a polymerase chain reaction test had no antibodies detected approximately 44 days after the diagnosis of COVID-19.¹⁷

In summary, it is difficult to objectively assess the scale of increased susceptibility to SARS-CoV-2 infection in the population treated with renal replacement therapy due to the differences in the research methodology used in the available studies and their observational nature. The incidence also varied over time, depending on the geographic region and the virus variant causing the infection at the time. Moreover, the epidemiology has been significantly influenced (improved) by a targeted policy to prevent the spread of infection and an increasing proportion of vaccinated people and convalescents.

Severe course of the disease

Asymptomatic infections in patients on dialysis accounted for 10% to 50% of COVID-19 cases, depending on the study population.^11,18,19 Interestingly, the baseline characteristics of the patients with asymptomatic and symptomatic infections did not differ, which may suggest that other, so far unidentified factors influence the course of COVID-19 in persons with CKD.¹⁹ The reason for such a large difference in the incidence of asymptomatic infections between different studies may be the previously mentioned underestimated number of infections in many reports due to the lack of widespread testing of patients. In our study, conducted in dialysis centers in the Pomeranian Voivodeship, where only symptomatic patients and those who had contact with infected individuals were obligatorily tested, the percentage of participants infected with SARS-CoV-2 and not presenting any symptoms of the disease was approximately 30%.²⁰ This rate is slightly lower than that observed in the general population according to the latest meta-analysis.²¹ The symptomatology of the disease changed during the pandemic with the evolution of the virus and its variants, as well as owing to the introduced vaccinations. The variants differed not only in terms of the structure and course of the induced disease but also in the degree of infectivity and the ability to avoid the innate and acquired immune reactions of the infected subject.²² So far, 5 variants of concern have been described for SARS-CoV-2: B.1.1.7 (Alfa), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), causing so far the most severe disease, and B.1.1.529 (Omicron), with the highest infectious potential but associated with a milder disease than the other variants. Symptoms of COVID-19 presented by patients treated with renal replacement therapy did not differ significantly from the ones manifested by individuals from the general population. However, the presence of symptoms in this group was reported less frequently than in patients without CKD, which could be associated with extensive disorders of the immune response or immunosuppressive treatment and, consequently, reduced reactivity.²⁰ In retrospective studies comparing the course of the disease of hospitalized COVID-19 patients treated with HD and PD, no differences were found between the 2 groups.^23,24 The most frequently reported symptoms were fatigue (70.6%), fever (44.7%), dyspnea (40%), and cough (30.6%). Fever, cough, and dyspnea were also reported in the majority of COVID-19–symptomatic KTRs. Also, 30% to 50% of the patients reported gastrointestinal complaints.^25,26 Whether or not SARS-CoV-2 could invade enterocytes and break the gastrointestinal mucosal barrier, thereby resulting in an increased risk for bacteria translocation and peritonitis in PD patients, is unknown.

It is noteworthy, however, that in the patients treated with renal replacement therapy, the disease progressed rapidly and was severe. As shown by the results of studies from our center, at the time of SARS-CoV-2 infection diagnosis, inflammatory changes in the lungs were present in almost 75% of HD patients, and almost 30% of them had at least 25% of the lung parenchyma involved. Importantly, advanced changes indicating a very rapid progression of the inflammatory process were found in as many as 62% of the patients.²⁰ In the general population, such changes were observed in 5% to 36% of patients with COVID-19.²⁷ This is reflected by the rapid course of the disease and shortening of the time between the onset of symptoms and death, which were observed in deceased HD patients.^28,29 As in the general population, the indicators of severe disease at diagnosis are fever, low blood oxygenation rates, elevated levels of inflammatory markers, and low levels of peripheral blood lymphocytes. Some observational studies indicate that high serum levels of 25-hydroxyvitamin D or chronic treatment with oral vitamin D preparations prior to the infection may be associated with a milder disease course in both renal replacement therapy and non–renal disease patients.^30,31 Although the gentle and prolonged removal of body fluids and toxins during PD may lower the risk of hemodynamic instability and hypervolemia that may further worsen oxygenation in individuals with COVID-19, it has not been proven that the course of the disease in PD patients is less severe.

A similarly rapid and severe course of the disease was observed in KTRs. Minimal or mild respiratory symptoms were often associated with radiographic signs of pneumonia, which were found in over 80% of the patients.^25,32 According to the available meta-analyses, 25% to 29% of the KTRs with symptomatic COVID-19 required admission to an intensive care unit.^33,34 In addition, acute kidney injury was more common in the KTRs hospitalized for COVID-19 than in the general population, and in some studies it was present in as much as 75% to 83% of cases.^35,36 A meta-analysis by Chen et al³⁷ estimated this rate to reach 43%. In the general population, the percentage of hospitalized patients with acute kidney injury did not exceed 9%.³⁸ A study found that KTRs hospitalized for COVID-19 required periodic dialysis 3.5 times more often than the general population.³⁹ Another observed complication in some KTRs with COVID-19 was acute transplant rejection, although its frequency, based on the available reports, did not appear to be high.³⁵ The pathogenetic mechanisms of all of these complications are complex. The underlying cause is probably direct damage to the kidneys by SARS-CoV-2. Other possible causes include damage to the vascular endothelium, coagulopathy and consequent thrombotic microangiopathy changes, and a cytokine storm.⁴⁰ Prerenal factors and hemodynamic consequences, cytomegalovirus and BK polyomavirus activation, or the consequences of the reduction of immunosuppressive therapy, which often occurred in the patients after confirmation of SARS-CoV-2 infection, cannot be excluded.^41-43 As shown in a meta-analysis, about 8% of the patients experienced graft loss.³⁷

The patients receiving renal replacement therapy who recovered from COVID-19 had delayed viral clearance, which was prolonged for an average of 18 days in HD patients, as compared with 11 days in individuals without kidney disease.^44,45 A similar situation occurred in KTRs.⁴⁶ This naturally translates into a longer hospitalization period among these patients.

Higher mortality

In 2020, during the initial period of the pandemic, the COVID-19 fatality rate among HD patients ranged from 15% to 30%, and was a lot higher than in the general population, where it did not exceed 2%.^10,47,48 As a result, the overall mortality among HD patients in many countries during this period was by 30% higher than in the previous years.⁴⁸ For example, the population of dialysis patients in the United States decreased by as much as 1.6% in 2020.⁴⁹ The epidemiological situation among Polish patients is illustrated by the results of a population study conducted in our center, covering all HD stations in the Pomeranian voivodeship.¹⁰ It showed that the mortality rate due to COVID-19 among HD patients during the second wave of the pandemic was as high as 30.4%. After taking into account the differences in the age of the respondents, it was over 5 times higher than in the general population of the same region of Poland.¹⁰ The indicators of increased risk of death from COVID-19 in this population included mainly older age, greater degree of patient fragility, and high comorbidity rate, in particular the presence of renal vascular disease, obesity, and heart failure.²

The COVID-19–related mortality among the KTRs was equally high and ranged between 21.3% and 32%, depending on the age of the patients and accompanying diseases.^2,32 After adjustment for asymptomatic infections, the mortality rates were lower and reached approximately 15%.¹⁶ The risk factors for death in this group of patients were older age, the presence of diabetes and cardiovascular diseases, and organ transplantation from a deceased donor^16,26,50 (Supplementary material, Table S1).

Serious sequelae of the disease

Recovering from COVID-19 does not solve all health problems of patients infected with SARS-CoV-2. In some individuals, certain symptoms persist for more than 12 weeks from the onset of the disease, despite viral eradication.⁵¹ Such a complication is referred to as a post-COVID syndrome. It affects the majority of survivors in the general population, according to studies performed at the beginning of the pandemic.⁵² Based on a meta-analysis of 15 244 hospitalized individuals and 9011 outpatients with COVID-19, it was calculated that at least 1 disease symptom persisted 90 days after the onset of the disease in more than 45% of the patients.⁵³ Studies in individuals treated with renal replacement therapy are sparse in this respect, but indicate that 6 months after the disease, the percentage of patients with the post-COVID syndrome may reach as much as 81% in the HD patients and 71% in the KTRs.^54,55 As in the general population, the most frequently reported persistent symptoms are fatigue and muscle weakness, which affected more than 40% of the study patients. Other reported symptoms include dyspnea, muscle ache, nausea, loss of appetite, memory deterioration, and sleep disturbances. The factors that distinguish patients undergoing renal replacement therapy from the general population are a long-lasting feeling of heart palpitations in the HD patients, as well as increased hair loss in the KTRs. Importantly, persistent symptoms significantly translate into a worse quality of life.^54,55 However, the reports on the post-COVID syndrome should be approached with caution. Most of them are observational, uncontrolled questionnaire studies, and the obtained results differ significantly, which is influenced by, among other things, differences in the characteristics of the study populations, severity of the disease, and the diagnostic methods used. In the case of HD patients, an additional factor hindering the interpretation of the results is the presence of a number of the abovementioned symptoms of the post-COVID syndrome regardless of COVID-19.

The impact of previous COVID-19 on the risk of SARS-CoV-2 reinfection in renal replacement therapy patients has not been widely studied. The results of one of the few studies on this issue conducted in a group of 2337 HD patients who had previously been infected with SARS-CoV-2 indicated a reduction in the risk of subsequent infections by 45%, and in the risk of symptomatic course of COVID-19 by 79%.⁵⁶ The difficulty in analyzing this relationship is related to the fact that most of the convalescent patients who were treated with renal replacement therapy were also subjected to prophylactic vaccinations. The results of this study also do not include an incidence analysis in the era of the spread of the virus variants with greater infectivity.

Worse response to vaccination

The invention of COVID-19 vaccines has significantly changed the course of the struggle with the pandemic. Due to the very severe disease, renal replacement therapy patients in many countries were referred for vaccination early, right after health care professionals. During the implementation of the vaccination program, certain differences in response to vaccination emerged, which necessitated an individualized approach and modification of the program in this group of patients.

The majority of the patients receiving renal replacement therapy were vaccinated with mRNA vaccines, which were available first, initially following the same 2-dose schedule as used in the general population. In HD individuals, a positive response to vaccination, as measured by seroconversion of IgG antibodies to the spike protein (S) after the second dose of the vaccine, was observed in 90% to 95% of cases—similarly to the rate obtained in the general population.⁵⁷ In fact, antibody titers analyzed 2 weeks after the vaccination were found to be significantly lower in the HD patients than in the general population, more than 10-fold in some studies.^58,59 Moreover, the serological response in the HD patients was significantly delayed.⁶⁰ Independent predictors of a weaker immune response to vaccination were low levels of albumin, IgG, and lymphocytes in the blood, use of immunosuppressants, older age, longer duration of dialysis treatment, use of high doses of intravenous iron, and prior serological failure to hepatitis B vaccine.^58-61 Some, but not all, studies have shown a better humoral response and higher postvaccination antibody titers in PD patients than in HD patients.^62-64 There are several explanations for the potentially better immunogenicity of the BTN162b2 vaccine (Pfizer) in the former group. In PD, during which the natural membrane is utilized, the use of biocompatible solutions has been associated with a better peritoneal host immune defense. It may well be that less pronounced inflammation, together with a better-preserved capacity to upregulate the counter-regulatory interleukins, which at least in part determine the immune competence, are responsible for the higher antibody response to the COVID-19 vaccine in PD patients.

Patients after kidney transplantation responded to vaccination much worse than those undergoing dialysis. Only about 50% of the KTRs achieved seroconversion in the range of anti-S antibodies after 2 doses of vaccination with the mRNA preparation. Additionally, the obtained antibody titer among the responders was much lower than in the general population.^65-67 The factor negatively determining the humoral response was, apart from the older age of patients, the immunosuppressive treatment, in particular its strength and the treatment protocol including induction with polyclonal antibodies and antiproliferative drugs from the mycophenolate group.^65,67,68 As in the case of patients treated with dialysis, a positive effect on the humoral response to the vaccine was due to a prior SARS-CoV-2 infection. Patients with documented SARS-CoV-2 infection in the past achieved anti-S antibody seroconversion with antibody levels similar to those obtained in the general population of people without prior COVID-19.^58,69 Moreover, a significant correlation was found between the strength of the immune response after vaccination and the severity of previous COVID-19 symptoms.⁶⁰ Several studies have shown better immunogenicity of the mRNA-1273 (Moderna) vaccine as compared with the BNT162b2 (Pfizer) vaccine in both HD patients and KTRs. This concerned both humoral and cellular responses.^60,65,70 It seems that the main reason is the difference in mRNA content between the 2 preparations. The mRNA-1273 preparation contains 100 µg of mRNA in a single vaccine dose, while BNT162b2 contains 30 µg. Additional elements differentiating both preparations are a longer interval between the administration of their 2 doses (4 weeks for mRNA-1273, and 3 weeks for BNT162b2) as well as better thermal stability of the mRNA-1273 preparation. Publications on the outcomes of using other vaccines in the renal replacement therapy population are rare and involve small patient groups. However, it seems that both AZD1222 (Astra Zeneca) and Ad26.COV2.S (Johnson & Johnson) vector vaccines are less immunogenic than the vaccines based on the mRNA platform.^71,72

Due to the worse response to vaccination, most scientific authorities recommended that the renal replacement patients be administered a third, supplementary dose of the mRNA vaccine already as part of the primary vaccination schedule, and a fourth, booster dose. The third dose of the vaccine, which was usually administered 1 to 2 months after the second dose, significantly increased antibody levels in the majority of dialysis patients.^73-75 In the KTRs, approximately 50% of those who did not respond to 2-dose vaccination achieved anti-S antibody seroconversion, thus raising the proportion of vaccine responders to nearly 75%.^76,77 Data on the persistence of the humoral response following vaccination in renal replacement therapy patients show a decline in the antibody titer at a rate similar to that observed in the general population.^62,73,76,78 A more sustained response was found at higher initial antibody titers, for example, in PD patients and in those vaccinated with mRNA-1273.⁷⁹

As in the general population, protection against subsequent SARS-CoV-2 virus variants emerging during the pandemic, measured by serum neutralizing activity, was lower than that against the wild-type version.^80-82 For example, a meta-analysis by Chen et al,⁸⁰ including studies carried out in the general population, showed that the neutralizing activity of the serum against the B.1.351 virus variant was as much as 2.5-fold lower than against the wild-type virus in individuals vaccinated with protein vaccines, 4.6-fold lower in those vaccinated with mRNA vaccines, and 7.1-times lower after vaccination with vector preparations.⁸⁰ In one of the few studies conducted on dialysis patients with confirmed post-vaccination neutralizing activity against the wild-type virus, only 63% showed similar activity against the variant B.1.351.⁸¹

Patients treated with renal replacement therapy were not recruited into large registry studies assessing the clinical efficacy of vaccination, that is, the real impact on reducing the risk of severe disease or death from COVID-19. We can therefore draw conclusions in this regard only on the basis of a small number of observational studies carried out in this population, and the incidence of breakthrough infections. For example, in an American analysis of more than 35 000 dialysis patients, the hazard ratios of COVID-19 post vaccination were 0.22 and 0.27, respectively, for individuals vaccinated with BNT161b2 and mRNA-1273 as compared with unvaccinated patients.⁸³ Similar results were obtained in an observational analysis carried out among dialysis patients from the Pomeranian voivodeship, which showed an almost 80% reduction in the incidence of COVID-19 among HD patients vaccinated with at least 2 doses of an mRNA vaccine (unpublished data). Clinical efficacy of vaccination among HD patients seems to be worse than in the general population, where the reduction in the incidence of symptomatic disease in vaccinated individuals was 97%, however, there is no doubt that vaccination resulted in a significant improvement in their prognosis.⁸⁴ There was also a significant reduction in the COVID-19 fatality rate (to around 7%) in the vaccinated HD patients who contracted COVID-19 during the subsequent, fourth wave of the pandemic. This reflects a significant improvement in prognosis in this population, especially as the dominant virus variant in the analyzed period was the Delta variant, which has been associated with the most severe disease so far. In the case of the KTRs, the real clinical efficacy of vaccination seems to be worse, which is undoubtedly due to the worse immune response to vaccines as discussed above. A Canadian population study of a cohort of 12 842 organ transplant recipients showed that 2-dose vaccination reduced the risk of hospitalization and death from COVID-19 by 54%. The third dose of the vaccine raised this rate to 67%⁸⁵ (Supplementary material, Tables S1 and S2).

Treatment

COVID-19 treatment strategies are gradually evolving. So far, the therapy is still largely supportive and focused on preventing complications. An important aspect is also the modification of immunosuppressive treatment, especially as it may contribute to the exacerbation of the underlying condition responsible for the kidney disease or cause rejection of a transplanted kidney. An overview of the most important drugs used in the treatment of COVID-19, including their use in the group of patients with CKD, is provided in Table 1.

**Table 1**. Overview of COVID-19 therapies in the general population and considerations regarding drug use in patients with chronic kidney disease^a
Therapy	Ambulatory care	Hospitalized: mild-to-moderate disease (without oxygen supplementation)	Hospitalized: severe disease (SpO₂ <⁠94% on room air)	Hospitalized: critical disease (mechanical ventilation, septic shock, and ECMO)	CKD
Corticosteroids	–	Suggested not to use	Suggested to use	Recommended to use	No changes
IL-6 receptor antagonist monoclonal antibody (tocilizumab)	–	–	Suggested to use if CRP >75 mg/	Suggested to use if CRP >75 mg/l	No changes
Remdesivir^b	–	–	Suggested to use; accumulation in ESRD?	Suggested not to use	Contraindicated if eGFR <⁠30 ml/min/1.73 m²
Monoclonal antibodies	Suggested to use^c: bamlanivimab / etesevimab, casirivimab / imdevimab, sotrovimab, bebtelovimab	–	–	–	No changes
JAK inhibitors	–	–	Suggested to use (clinical improvement); accumulation in ESRD?	Suggested not use	Dosage depending on eGFR; barcitinib contraindicated if eGFR <⁠30 ml/min/1.73 m²
Barcitinib + corticosteroids	–	–	Suggested to use: barcitinib 4 mg per day (for 14 days or until hospital discharge)	–	Barcitinib: eGFR 30–59 ml/min/1.73 m², 2 mg per day; contraindicated if eGFR <⁠30 ml/min/1.73 m²
Nirmatrelvir / ritonavir^d	Suggest to use (see: CKD)	–	–	–	eGFR >60 ml/min/1.73 m², 300/100 mg every 12 h for 5 days; eGFR 59–30 ml/min/1.73 m², 150/100 mg every 12 h for 5 days; eGFR <⁠30 ml/min/1.73 m², not recommended
Molnupiravir	Suggested to use: 800 mg for 5 days	–	–	–	No changes
Modified from the Infectious Diseases Society of America and European Respiratory Society Treatment guidelines (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/, accessed August 21, 2022). a No RCTs in COVID-19 patients with CKD b Not recommended by the European Respiratory Society guidelines c In patients with mild-to-moderate COVID-19 at high risk for progression to severe disease d Interactions with immunosuppressants (check Summary of Product Characteristics) Abbreviations: CKD, chronic kidney disease; CRP, C-reactive protein; ECMO, extracorporeal membrane oxygenation; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; JAK inhibitors, Janus kinase inhibitors; IL-6, interleukin-6; RCT, randomized controlled trial; SpO₂, oxygen saturation

Challenges

Despite the fact that the dramatic fight against the COVID-19 pandemic (which has already claimed over 4 million victims worldwide) has been going on for more than 2 years and enormous financial resources have been spent on research, many aspects related to the disease still remain unclear. Particularly in relation to patients treated with renal replacement therapy there are many issues that require examination and consensus on the rules of conduct. This matter becomes urgent with the virus continually mutating and the next fall wave of infections looming. Recently, an increase in the number of infections has been observed due to the emergence of another virus variant known as BA.2.75, also referred to as Centaurus, which is spreading rapidly around the world. The large number of mutations located in the areas associated with the spike protein in this variant is worrying, as it may help the virus bypass the immune mechanisms developed following vaccination or prior infection. It is not known yet whether this variant causes severe disease.

There remains an open question about the optimal schedule of primary immunization and the rules for administering booster doses. It is recommended to use a booster dose 5 to 6 months after completion of the primary vaccination schedule (ie, 3 doses in patients treated with renal replacement therapy). However, studies indicate that the rate of reduction of antibodies in HD patients 3 months after vaccination may exceed 80%.⁷³ Other studies suggest that an anti-S antibody titer of 264 BAU/ml is associated with an 80% reduction in the risk of symptomatic COVID-19 caused by the Alpha variant in the general population, and is considered protective by some.⁸⁶ It is not known, however, whether these observations can be extrapolated to patients treated with renal replacement therapy and whether the ability to neutralize this antibody titer also applies to the Delta and Omicron variants. As already mentioned, some studies support the use of preparations with a higher dose of mRNA. It is also unknown whether stronger immunogenic effects may be exerted by vaccines containing the entire inactivated virus particle, and thus a greater number of potentially immunogenic epitopes.⁸⁷ Recently, the European Medicines Agency has approved the first such vaccine on the European market (VLA2001). We also have no experience with an adjuvanted protein vaccine (Novavax), produced according to classic technology, which has been used with good results in the general population.⁸⁸ Further questions raised in some studies on the general population concern the higher effectiveness of heterogeneous vaccination schedules, that is, combining vaccines with 2 different mechanisms of action (eg, mRNA and vector vaccines) in a single schedule.⁸⁹ Despite the use of the third, supplementary dose of the mRNA vaccine against COVID-19, still about a quarter of KTRs and a few percent of HD patients do not respond to vaccination, that is, are not protected against the virus and the consequences of COVID-19. Some studies point to the effectiveness and justification for the use of subsequent supplemental doses in this population.^90,91

The question of the legitimacy and principles of applying pre-exposure prophylaxis remains open. This type of primary prophylaxis relies on the repeated administration of a combination of long-acting monoclonal antibodies (mAbs) targeting different viral epitopes. Preliminary studies in KTRs who did not respond to vaccination indicate that such management may reduce the risk of symptomatic COVID-19.^92,93 A study by Ducloux et al⁹³ showed that subcutaneous administration of REGEN-Cov (casirivimab + imdevimab) at 4-week intervals resulted in a high titer of neutralizing antibodies in the serum and protection against infection with the Delta variant in the KTRs who had not responded to vaccination previously. Prophylaxis carried out in this way is not associated with significant side effects but the efficacy of this combination may be reduced in individuals infected with the recent Omicron variant.⁹⁴ Reduced risk of the disease in KTRs during the pandemic waves when Omicron dominated was confirmed for the combination of tixagevimab + cilgavimab (Evushled) mAbs.⁹⁵Protection against symptomatic infection was stronger for several months with a higher dose of these mAbs and seemed to be even more effective than in vaccinated solid organ transplant recipients.⁹⁶ It seems reasonable to consider such a procedure in the KTRs who did not respond or had a poor immune response to vaccination as well as in those requiring induction treatment, including previously desensitized individuals.

As in the case of the general population, there are no recommendations based on research evidence on how to vaccinate patients treated with renal replacement therapy who have already contracted COVID-19. It is known from observations in people without CKD that acquired immunity in convalescents is at least as strong and durable as the one obtained after COVID-19 vaccination. It is also known that stronger protection against infection is seen in convalescents who have received at least 1 dose of a COVID-19 vaccine.⁹⁷ It should be emphasized, however, that a history of COVID-19, with or without additional vaccination, does not completely protect against subsequent infections, especially with the recently dominant, highly infectious Omicron variant.^98,99 Therefore, in the population of patients treated with renal replacement therapy, regardless of previous disease incidence, it seems reasonable to apply the full course of vaccination actually consisting of 3 primary doses and a booster dose. The number of boosters in immunocompromised patients will probably increase; such a strategy has been quite recently proposed in the United States by the Centers for Disease Control and Prevention¹⁰⁰. Treatment of COVID-19 also remains an open field for further research. Patients treated with renal replacement therapy have not been included in large clinical trials in this area so far. Therefore, all recommendations in this regard in these patients derive from the extrapolation of the results of studies conducted in the general population.

Summary

The consequences of the COVID-19 pandemic, which so dramatically affected the fate of patients with CKD, particularly those treated with renal replacement therapy, informed numerous studies focused on finding effective preventive and therapeutic measures that would significantly improve the prognosis in this group of patients. Despite progress in this regard, many questions still remain to be answered. The primary challenge is still to reduce the incidence of new infections as well as reinfection in convalescents and vaccinated individuals by optimizing vaccination schedules. The impact of COVID-19 sequelae, including the post-COVID syndrome, on the survivors should also be investigated, especially whether this complication is an additional source of morbidity in the population with an already poor prognosis. The safety and efficacy of new COVID-19 drugs should be assessed taking into account the patients treated with renal replacement therapy. Patients with CKD, and especially those undergoing renal replacement therapy, may be among those who will benefit most from early intervention, given that the immune response to vaccines is weakened, and mortality from COVID-19 is very high in this group.

Supplementary material.pdf

Correspondence to

Leszek Tylicki, MD, PhD, Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, ul. Dębinki 7, 80-952 Gdańsk, Poland, phone: +48 58 584 47 00, email: leszek.tylicki@gumed.edu.pl

Received

July 28, 2022.

Revision accepted

August 26, 2022.

Published online

September 9, 2022.

Acknowledgments

None.

Funding

None.

Conflict of interest

None declared.

How to cite

Biedunkiewicz B, Dębska-Ślizień A, Tylicki L. COVID-19 in patients requiring renal replacement therapy: an overview of current data and future challenges. Pol Arch Intern Med. 2022; 132: 16336. doi:10.20452/pamw.16336

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