key: cord-0903917-ef9ho8sv
authors: El Karoui, Khalil; De Vriese, An S.
title: COVID-19 in dialysis: clinical impact, immune response, prevention and treatment
date: 2022-02-14
journal: Kidney Int
DOI: 10.1016/j.kint.2022.01.022
sha: 8b396e3b5049ae10b3245b78c05d140198d09111
doc_id: 903917
cord_uid: ef9ho8sv

The SARS-CoV-2 pandemic has profound adverse effects on the dialysis population. Patients requiring dialysis are at increased risk of SARS-CoV-2 infection and mortality, and many have experienced psychological distress, as well as delayed or suboptimal care. COVID-19 survivors have prolonged viral shedding, but generally develop a robust and long-lasting humoral immune response that correlates with initial disease severity. However, protection against reinfection is incomplete. A growing body of evidence reveals delayed and blunted immune responses to SARS-CoV-2 vaccination. Administration of a third dose within 1-2 months of prime-boost vaccination significantly increases antibody levels, in particular in patients with poor initial responses. Patients on dialysis have inferior immune responses to adenoviral vector vaccines than to mRNA vaccines. The immunogenicity of the mRNA-1273 vaccine is markedly better than that of the BNT162b2 vaccine, most likely by virtue of its higher mRNA content. Despite suboptimal immune responses in dialysis patients, preliminary data suggest that vaccination partially protects against infection and severe disease requiring hospitalization. However, progressive waning of immunity and emergence of SARS-CoV-2 variants with a high potential of immune escape call for a booster dose in all dialysis patients 4-6 months after prime-boost vaccination. Patients with persistent poor vaccine responses may be candidates for primary prophylaxis strategies. In the absence of specific data in dialysis patients, therapeutic strategies in the event of established COVID-19 must be extrapolated from evidence obtained in the non-dialysis population. Neutralizing monoclonal antibodies may be an attractive option after a high-risk exposure or during the early course of infection.

patients with very mild to severe COVID-19. The main symptoms include fatigue, dyspnea, cardiac involvement, muscle ache, headache, joint pain, or neuropsychological disorders. Since these symptoms commonly occur in dialysis patients, the prevalence of long COVID is difficult to assess. A recent study in 183 surviving hemodialysis patients with 6-month follow-up after the acute infection identified no excess cardiovascular disease or mortality, but severe cachexia and extreme muscle weakness in 13% of patients 24 .

In early 2020, an excess mortality of 15-20% (corresponding with 7.000-10.000 deaths) was observed in the US dialysis population 25, 26 . In contrast, other regions reported no overall excess mortality, because COVID-19-related mortality was balanced by lower than anticipated mortality in noninfected dialysis patients, possibly by a lower incidence of other respiratory infections by virtue of droplet-infection prevention measures 1 . Although regional disparities were observed, in the US the number of incident patients and the mean estimated glomerular filtration rate at dialysis initiation were significantly lower in 2020 than in previous years, particularly in elderly patients and non-Hispanic Blacks 27, 28 . Overall, the size of the US dialysis population shrunk by 1,6% in 2020 29 .

The rate of hospitalization unrelated to COVID-19 also declined significantly 25 , suggesting difficulties in accessing care. In addition, logistical constraints during the first wave resulted in decreased weekly dialysis time in non-infected patients 30 . Furthermore, a sharp reduction in kidney transplantation occurred during the first wave in 22 countries worldwide 31 . Although data on the benefit of renal transplantation during the pandemic are conflicting 32, 33 , many transplantation programs were interrupted. Finally, dialysis patients have experienced major psychological distress due to exposure to a new disease without effective treatment and high case-fatality rates 34 .

A critical challenge is to identify valid and reproducible biomarkers of the humoral and cellular immune responses to infection or vaccination ( Figure 1 ) and link these to clinical outcomes. has attempted to introduce standardization by virtue of the WHO International Standard study 35 , that provides the mathematical relationship of the individual test units to the WHO binding antibody units.

The key question is whether antibody levels can serve as a valid surrogate marker for protection against (re)infection. Data from seven large vaccination trials and a convalescent cohort revealed a strong relationship between neutralization antibody levels early after vaccination or infection and subsequent protective efficacy 36 , suggesting the higher the antibody levels, the better the protection from (re)infection. The estimated neutralizing antibody level required for protection from severe disease appeared to be about six fold lower than the level required for protection from any symptomatic infection 36 . A large study in vaccinated health care workers revealed that the risk of a breakthrough infection was associated with the neutralizing antibody titer during the peri-infection period, but even stronger with the peak neutralizing antibody titer following vaccination 37 , corroborating the value of neutralizing antibody levels as an immune correlate of protective efficacy. A threshold of 264 binding antibody units (BAU)/ml, which is associated with a 80% protection against symptomatic COVID-19 caused by the Alpha variant, is currently considered as protective 38 .

The emergence of the VOC has added a layer of complexity to the assessment of the humoral response. First, the commercially available anti-S and anti-RBD ELISA tests have been designed based on the S protein sequences of the original virus that were deposited in January 2020. As such, they may not capture all antibodies that are generated against severely mutated S proteins and thus underestimate the strength of the natural humoral response to the VOC. Conversely, levels of antibodies induced by vaccines based on the S protein sequences of the original virus may overestimate the true effectiveness of vaccine-induced humoral immunity against the VOC.

The cellular immune response is likely an important component of the protective adaptive immunity, but its assessment is labor-intensive and beyond the abilities of a routine clinical laboratory. Quantification of SARS-CoV-2 specific cellular immunity requires stimulation of whole blood with SARS-CoV-2 peptide pools. Subsequently, proliferation of specific lymphocyte subpopulations, activities of certain signaling pathways or generation of a number of cytokines (e.g. interferon-gamma, interleukin-2) are measured. For none of these tests, the cut-off value that correlates with protection against infection is known. CKD, with impaired kidney function as independent predictor of time to viral clearance 39 . More than two thirds of hemodialysis patients remained PCR positive 20 days after symptom onset 40 . Existing symptom-and time-based strategies to inform the decision to lift quarantine may therefore not be applicable to the dialysis population. The challenge is to differentiate between the presence of remnant viral RNA and replicationcompetent (and therefore infectious) virus, since unnecessary prolonging of isolation has adverse logistical and psychological effects. Although no single laboratory method can serve as a reliable predictor of viral infectivity, there is a strong association between quantitative viral load data, PCR cycle threshold values and the ability to recover SARS-CoV-2 in viral culture 42 . A pragmatic approach could be to discontinue quarantine when the viral load is below 100.000 copies/mL, corresponding with a cycle threshold value of greater than 28-31, depending on the type of analyzer (e.g. COBAS 6800, RespiTAC, Genexpert) and gene target (N, Orf-1, RdRP, E) (Marijke Reynders, personal communication).

Following natural SARS-CoV-2 infection, the large majority of hemodialysis patients develop a robust antibody response 41, [43] [44] [45] [46] [47] [48] [49] [50] [51] . These observations are somewhat counterintuitive in view of the high mortality rates of COVID-19 in the hemodialysis population and may be partially accounted for by survivor bias, since humoral responses may be better in patients that have recovered from SARS-CoV-2 infection. An alternative explanation may be that hemodialysis patients develop more severe disease, produce higher levels of pro-inflammatory cytokines and have prolonged viral shedding, resulting in more intense immune stimulation. Indeed, hemodialysis patients with a history of severe PCR-confirmed SARS-CoV-2 infection requiring hospitalization had higher antibody levels than patients that developed only mild or asymptomatic disease, but the decay trajectory of the antibodies was similar in both groups 52 . Likewise, symptomatic patients had higher antibody levels than asymptomatic individuals 45, 46 . Lack of seroconversion has been observed in 5-10% of hemodialysis patients [43] [44] [45] and could mainly be attributed to immunosuppressive drugs or chemotherapy 43 .

Most studies show durable humoral immune responses in hemodialysis patients with a slow decline over time 43, 44, 46, 47, 49, 51, 52 and a longevity that is commensurate with that of the general population. Serological responses have been reported to persist up to more than 1 year, with a faster decay of anti-N IgG than anti-S IgG 52 .

of subsequent SARS-CoV-2 infection and clinically manifest COVID-19, respectively 54 . For comparison, a large prospective study in health care workers found that antibody positivity conferred a nearly 90% reduction of the risk of reinfection 55 .

The impact of the cellular response on the risk of reinfection in dialysis patients remains ill-defined.

It should be noted that the reported studies have been conducted when the wild-type virus was the most prevalent strain. The ability of naturally acquired immunity to prevent reinfection with the Delta and Omicron VOC has not been studied in dialysis patients.

A recent elegant review summarized 22 studies reporting on early seroconversion rates after COVID-19 mRNA vaccination in patients receiving hemodialysis, 11 of which included a control group generally consisting of health care workers 56 . Not included in this review are two large multicenter studies 57, 58 , as well as a number more recently published smaller studies [59] [60] [61] [62] .

The emerging picture is that the development of the serological response in dialysis is substantially delayed. In healthy volunteers, the peak response was achieved at 4/5 weeks after the first vaccine dose with stable values thereafter, while antibody titers continued to rise in hemodialysis patients 58 .

The pooled estimate of the antibody response rate in patients receiving hemodialysis was 45% and 89% after the first and second dose, respectively 56 . At first sight, response rates after the second dose do not compare unfavorably with 95-100% seroconversion rates in healthy controls. However, seroconversion rates only describe the proportion of patients that cross the detection limit of the antibody test, but do not provide information on the size and quality of the humoral response. Indeed, antibody levels are significantly lower in hemodialysis patients than in healthy volunteers 58,63-69 . As an example, 8 weeks after BNT162b2 (Pfizer-BioNTech) vaccination only 26% of COVID-19 naïve hemodialysis patients but 84% of COVID-19 naïve healthy volunteers achieved a titer above 590 BAU/mL 58 .

In multivariate analyses, use of immunosuppressive drugs, low serum albumin, low lymphocyte count, low IgG levels, hepatitis B vaccine nonresponder status, high dialysis vintage and high intravenous iron dose were identified as independent predictors of a poor serological response 58, 61, 70, 71 . Age was retained as an independent predictor in some 59, 61, 68, 71 but not all studies 58, 70 , possibly due to differences in the type and number of parameters included in the multivariate analyses. It is tempting to speculate that markers of immunosenescence may be better predictors of the immune response than chronological age per se. Antibody titers were numerically higher in peritoneal dialysis than in hemodialysis patients in some [72] [73] [74] , but not all studies 75, 76 .

COVID-19 experience results in a strong vaccine-induced response 56, 58, 59, 61, 62 . Overall, the response in COVID-19 experienced dialysis patients was in the same range as that of COVID-19 naïve healthy volunteers, but a significant correlation was found between the intensity of the vaccineinduced immune response and the severity of the historic SARS-CoV-2 infection 58 .

A third vaccine dose, generally given 1-2 months after the second dose, significantly increased antibody levels in almost all dialysis patients [77] [78] [79] [80] [81] [82] . Patients with poor initial responses appeared to derive the most relative benefit, while those with high antibody titers after the second dose featured more modest increases 83 . Interestingly, serum from patients with an absent or low response after the second dose who subsequently received a third dose had a greater neutralizing capacity than serum of patients with a high response to standard prime-boost vaccination 82 . The response to the booster dose was similar in hemodialysis and peritoneal dialysis patients 79 .

Protection against the SARS-CoV-2 VOC may require higher antibody levels. Studies conducted in the general population revealed that the vaccine-induced neutralizing activity was only mildly reduced against Alpha, but 5 to 12-fold lower against Beta, 5-fold lower against Gamma, 6fold lower against Delta and 10-fold lower against Omicron, compared to the activity against wild-type viruses [84] [85] [86] [87] . Data in hemodialysis patients are limited. The neutralizing activity of serum taken 3 weeks after the second BNT162b2 or mRNA-1273 dose in dialysis patients was significantly lower against Beta than Alpha 88 , and against Delta than the wild-type virus 89 . Although BNT161B2 vaccination induced comparable neutralizing response against VOC in dialysis and non-dialysis patients, the adenoviral-based vaccine AZD1222 (AstraZeneca) had lower immunogenicity 90 . While a third vaccine dose induced neutralizing antibodies against the wild-type virus in the large majority of patients, less than a third developed neutralizing antibodies against Delta 82 .

Data on the longevity of the humoral response to vaccination in dialysis patients are rapidly emerging (De Vriese et al., submitted) 74, 76, [91] [92] [93] [94] [95] (Table  1) and reveal a gradual waning of antibody levels with a rate of decline similar to that in the general population. Not unsurprisingly, more durable responses were observed when the initial titers were higher, e.g. in peritoneal dialysis patients and in mRNA-1273 vaccine recipients 93 .

Prime-boost mRNA vaccination induced CD4+ T cell responses in 60-100% of dialysis patients, a proportion that is similar or slightly reduced compared to controls [57] [58] [59] 61, 66, 96, 97 . The magnitude of the CD4+ T cell response in hemodialysis patients paralleled that in controls in some 57, 67 but not all studies 58 . S-specific CD4+ T cell responses generally 57-59,96 but not always 61 correlated with anti-RBD IgG, in line with the cooperation between CD4+ T cells and B cells to generate IgG. Factors independently associated with CD4+ T cell responses included prior SARS-CoV-2 exposure, immunosuppression, nutritional status, lymphopenia and dialysis vintage 58 . CD8+ T cell responses were observed in less than 50% of dialysis patients, a proportion similar to that in healthy controls 59 . Factors negatively associated with CD8+ T cell responses included immunosuppression and absence of humoral response 59 .

In a cohort of 23 dialysis patients, a third vaccine dose led to an increase of CD4+ T cells specific for the wild-type and Delta variant. No effect on CD8+ T cells was observed 82 . However, in another study of 75 dialysis patients, the third dose given within 3 months after the second dose did not significantly affect the CD4+ T cell response, even after stratification for responder status after the second dose 83 .

A study of the B cell response in 44 dialysis patients 7 days after a BNT162b2 boost revealed impaired induction of effectors of B cell immunity (e.g. memory B cells and plasmablasts) compared to healthy controls, in line with the defective antibody response 65 . In contrast, another study found a similar proportion of RBD-specific memory B cells 1-2 months after a BNT162b2 boost in dialysis patients and controls, despite lower antibody levels in dialysis patients (El Karoui, submitted data). While a third dose, given 3.5 months after the second dose, induced a strong RBDspecific memory B cells expansion in SARS-CoV-2 naïve patients, this B cell compartment remained unchanged in SARS-CoV-2 experienced patients, suggesting no benefit of an early third dose in these patients.

In accordance with data in health care workers 98 , several studies reported a remarkably better immunogenicity of the mRNA-1273 vaccine (Moderna) compared with the BNT162b2 vaccine in hemodialysis patients 57, 58, 70, 99 . As an example, geometric mean antibody titers were significantly greater and a larger proportion of patients achieved the threshold of 590 BAU/ml with the mRNA-1273 vaccine (573 BAU/ml and 53.6%) as compared to the BNT162b2 vaccine (221 BAU/ml and 31.8%) 8/9 weeks after the first dose 58 . Similarly, cellular responses were more robust in mRNA-1273 than in BNT162b2 recipients 58, 61 . Both mRNA vaccines consist of mRNA encoding for the SARS-CoV-2 spike glycoprotein encapsulated in lipid nanoparticles and have no other content relevant to immunogenicity. However, the mRNA dose of mRNA-1273 (100 μg) is substantially higher than that of BNT162b2 (30 μg). Additional discriminatory elements are the longer interval between priming and boosting for mRNA-1273 (4 weeks) than for BNT162b2 (3 weeks) and a better thermostability and ease of handling of the former. Both mRNA vaccines showed near maximal clinical efficacy in large randomized trials 100, 101 , but the results were obtained on the short-term in healthy volunteers when the wild-type virus was dominant. Whether the better immunogenicity of the mRNA-1273 vaccine will translate into superior protection of vulnerable populations in the context of waning immunity and more resistant SARS-CoV-2 variants remains to be determined.

Data on the immunogenicity of the other vaccine platforms in the hemodialysis population are scarcer. The neutralizing ability of serum obtained in 178 COVID-19 naïve hemodialysis patients 33 days after full vaccination with BNT162b2 or AZD1222 was assessed in vitro 90 . Compared to BNT162b2 recipients, AZD1222 recipients had a markedly lower capacity to neutralize Alpha (>4-fold reduction), Beta (>3-fold reduction) and Delta (>6-fold reduction) 90 . Another study found a non-significant lower seroconversion rate in AZD1222 recipients (70.6%) than in BNT162b2 recipients (81.8%) 102 The durability of the serological response correlates with the robustness of the initial response. Among 1567 COVID-19 naïve dialysis patients, 67.5% of Ad26.COV2.S, 32.1% of BNT162b2 and 12.3% of mRNA-1273 recipients had undetectable antibodies 4 months after vaccination 93 . Likewise, in a cohort of 2563 COVID-19 naïve dialysis patients, anti-RBD antibodies had disappeared in 57% of Ad26.COV2.S recipients 4-5 months after vaccination and in 31% and 11% of BNT162b2 and mRNA1273 recipients 5-6 months after vaccination 92 .

Since there are currently no universally accepted and validated biomarkers for protection against SARS-CoV-2 infection, disease and mortality, only data on the incidence and severity of breakthrough infections (i.e. infection >2 weeks after full vaccination) can provide definitive answers on the real-world effectiveness of the COVID-19 vaccines. Reliable data are notoriously difficult to obtain, since the degree of vaccination of the general and dialysis population, the infectiousness and virulence of the prevalent SARS-CoV-2 VOC, and the local dynamics of the epidemic all have to be taken into account. In a retrospective cohort of more than 35.000 dialysis patients from the US, the hazard ratio for COVID-19 diagnosis was 0.22 and 0.27 after BNT161b2 and mRNA1273 vaccination respectively, as compared to propensity matched unvaccinated controls 103 . Modeling of data from hospitalizations following a SARS-CoV-2 infection in 3.620 dialysis patients and 457.160 people from general population in France revealed a reduced hospitalization rate in the dialysis population over time that was independently associated with vaccination coverage of dialysis patients and their same-age peers from the general population 104 . In a cohort of 15.251 maintenance dialysis patients observed between February 1 and August 26, 2021, fully vaccinated patients were significantly less likely to be diagnosed or hospitalized with COVID-19 105 . Nevertheless, 26% of new SARS-CoV-2 infections, 27% of COVID-19 related hospitalizations and 33% of COVID-19 related deaths occurred among fully vaccinated patients. The vast majority of these had very low or undetectable antibody levels at the time of COVID-19 diagnosis, generally because they had never developed an initial humoral response 105 . Breakthrough infections particularly occurred when Delta became the dominant strain and were most common among Ad26.COV2.S recipients and least common among mRNA-1273 recipients 105 . In another cohort of 2563 vaccinated patients requiring dialysis, 56 breakthrough infections (of which 25 required hospitalization) were identified after a median time from vaccination of 110 days, in particular in patients with low peak and peri-infection anti-RBD antibody levels 92 . Taken together, preliminary data reveal a substantial but incomplete clinical effectiveness of the SARS-CoV-2 vaccines in dialysis patients.

The presence of antibodies does not automatically track with functional humoral or cellular immunity required for long-term protection against SARS-CoV-2. However, they are currently the best surrogate markers to design and validate the optimal vaccination strategy in patients on dialysis (Figure 2 ). The extant evidence suggests that not all vaccines are created equal. Hemodialysis and other vulnerable populations with blunted vaccine responses should therefore receive the most immunogenic vaccines, in casu the mRNA vaccines. The observed differences between mRNA-1273 and BNT162b2 suggest a cardinal role for dose and may be conducive to the future development of high dose vaccines.

An additional dose administered with an interval of at least 4 weeks after the second dose appears especially effective in patients with initially poor or absent responses. As such, patients with a documented poor response or at high-risk for a poor response based on their clinical profile may be candidates for an additional vaccine dose. The progressive waning of immunity and appearance of VOC with a high potential of immune evasion is prompting the administration of a booster dose 4-6 months after prime-boost vaccination in all dialysis patients. A small subgroup (estimated to represent 5-10% of the dialysis population) will not mount a protective response following such an approach. As further vaccine doses are unlikely to be effective, these patients may instead benefit from pre-exposure prophylaxis, although monitoring the effectiveness of this strategy against future variants will require further studies. A combination of two long-acting monoclonal antibodies (tixagevimab and cilgavimab, AZD7442, Astra-Zeneca) that target two distinct RBD epitopes was associated with a 83% reduction of symptomatic COVID-19 at 6 months in a primary prevention setting (PROVENT trial) 106 . Nasal administration of the potent anti-SARS-CoV-2 agent niclosamide is currently evaluated as a means to prevent COVID-19 in vulnerable patient populations, including patients on dialysis (PROTECT-V, NCT04870333).

Finally, ring vaccination of household members and other close contacts is mandatory in dialysis patients, particularly in those with a suboptimal response to vaccination 104 .

The continuous emergence of VOC that partially evade the immune response to vaccines based on the original virus strain presents a gargantuan challenge to vaccine development. An updated mRNA-1273 vaccine encoding for the spike protein of Beta was highly effective in animal models 107 . In the meantime, however, Beta has been completely replaced by the far more contagious Delta and Omicron and is therefore no longer clinically relevant. Several companies have already announced the development of an Omicron-specific vaccine [108] [109] [110] . Preliminary evidence fortunately reveals a greatly increased neutralization efficiency after receipt of a third vaccine dose 111, 112 . Ultimately, we may need second-generation coronavirus vaccines that protect against all known and future VOC. A fascinating study from Singapore found that serum from survivors of the SARS outbreak in 2002-2003 that were vaccinated with BNT162b2 had the ability to neutralize SARS-CoV-1, all SARS-CoV-2 variants, as well as several bat and pangolin coronaviruses with potential to cause human infection 113 . These findings suggest that it must be feasible to develop a pan-sarbecovirus vaccine, through a mechanism of cross-clade boosting. Finally, the potential role of intranasal vaccines has garnered attention by the observation that viral loads are similar in the nose of vaccinated and unvaccinated individuals with SARS-CoV-2 infection 114 . Intranasal vaccine delivery may to induce mucosal immunity in the respiratory tract, reduce viral shedding in the nose and thus block viral transmission.

The short-term side effects of vaccines are less common and severe in patients on hemodialysis than in healthy volunteers 58 , commensurate with their immunogenicity in these populations. The tolerance of the second and third vaccine doses in patients on hemodialysis appears similar 79 .

Severe side effects are rare in the dialysis population. In an online survey from the US, 20% of responders reported vaccine hesitancy, about half of which expressed concerns about side effects 115 . The odds of vaccine hesitancy were higher among younger, female, Black, Native American or Pacific Islander patients 115 .

Treatment strategies for COVID-19 are rapidly evolving. As for now, therapy is still largely supportive and focused on prevention of complications.

Since SARS-CoV-2 S interacts with ACE2 to enter host cells, the role of renin angiotensin system (RAS) blockers in SARS-CoV-2 severity has been the subject of intense research. In a French nationwide study of almost 2 million hypertensive people, RAS blockers were associated with a 16-26% lower risk of hospitalization for COVID-19 compared to calcium channel blockers 116 . However, these results were not reproduced in other nationwide studies 117 . Moreover, losartan introduction did not reduce hospitalization rate in a RCT of 117 patients with mild symptomatic COVID-19 118 . Data in the dialysis population are scarce. In a retrospective cohort of 248 dialysis patients with COVID-19, RAS blockers were associated with a 50% reduced risk of mortality after propensity score matching 119 . However, data from the ERA-EDTA registry obtained in 1052 dialysis patients with COVID-19 disclosed no modification of fatality risk by RAS blockers after multiple adjustments, despite a trend towards a lower rate of hospitalization 120 . To date, no evidence suggests that RAS blockers should be introduced or discontinued after COVID-19 diagnosis in dialysis patients, unless in case of obvious contra-indication.

Thrombotic events are a major cause of COVID-19 morbidity 121, 122 . Dialysis patients with COVID-19 may experience arteriovenous fistula thrombosis 123 , mechanical dysfunction of the catheter or circuit clotting 124, 125 , although no excess of vascular access thrombosis was observed in another study of 601 patients with arteriovenous fistula/graft 126 . Prophylactic anticoagulation is an essential therapeutic strategy for dialysis patients, in accordance with recommendations for the non-dialysis population. Anticoagulation protocols are derived from those in the general population 127 , and adapted to the dialysis modality (intermittent versus continuous) and ventilation/oxygenation procedures in critically ill patients 122 .

Since March 2020, numerous therapeutic strategies to control COVID-19 have been or are currently under investigation ( Table 2 ). Only those shown to be effective and officially recommended by the Infectious Diseases Society of America (IDSA) or European Respiratory Society (ERS) will be discussed (Table 3) 128 . Since most prospective therapeutic trials have excluded dialysis patients for safety reasons 129 (including studies of novel antivirals against SARS-CoV-2 with promising results 130 ), therapeutic strategies in dialysis patients are extrapolated from evidence obtained in the non-dialysis population.

Glucocorticoids are now standard treatment in patients with severe to critical disease , by virtue of their benefit in the hyperinflammatory phase of COVID-19 131 . Interleukin-6 receptor antagonists (tocilizumab and sarilumab) are proposed in hospitalized patients with severe or critical illness and elevated inflammation markers, with the intention to limit the hyperinflammatory syndrome 132 . The JAKi baricitinib and tofacitinib are proposed in patients with severe non-critical disease.

Remdesivir, a nucleotide analog that inhibits SARS-CoV-2 RNA transcription, has shown limited benefit in hospitalized patients needing oxygen supplementation, but not in patients on invasive ventilation or ECMO 133, 134 . Remdesivir and its active metabolites are predominantly eliminated by the kidneys. Remdesivir was well tolerated in an observational study of 48 dialysis patients with SARS-CoV-2 infection 135 .

Neutralizing monoclonal antibodies targeting the RBD of the spike protein to inhibit virus entry in host cells are a therapeutic option in ambulatory mild to moderate COVID-19 at high risk of progression [136] [137] [138] [139] , but may be less effective in already hospitalized patients 140 . The efficacy of neutralizing antibodies against Delta and Omicron are the subject of intense research 141 . Neutralizing antibodies are well tolerated and no evidence suggests specific adverse effects in dialysis patients. Concerns have been raised regarding the selection of resistant SARS-CoV-2 variants in immunocompromised patients, including dialysis patients 142 . Although no studies have been performed specifically in the dialysis population, they represent an attractive option after a high-risk exposure or during the early course of infection.

The dramatic impact of the SARS-CoV-2 pandemic on the dialysis population has stimulated collective efforts to unravel the pathophysiology of COVID-19 and develop effective preventive and therapeutic measures. An optimized vaccination strategy and actions to improve vaccine acceptance clearly have the best chances at success, along with continued attention to droplet infection prevention measures. Patients with inadequate responses to vaccination may be candidates for a primary prevention strategy. The prevalence of long-lasting physical and neuropsychological consequences of past infection, the protective efficacy of natural and vaccine-induced immunity against new virus variants, and the long-term consequences of the pandemic on a population scale are among the many subjects that require further research. The fight against this pandemic is far from over.

The authors declare no conflict of interest. Viral proteins are taken up by antigen presenting cells (APC) that generate a range of pro-inflammatory cytokines. The antigens are presented to naïve T cells, that differentiate into different types of cells. T follicular helper (TFH) cells assist B cells to differentiate into plasma cells that produce antigen-specific antibodies to neutralize the virus. A broad range of antibodies are generated against multiple epitopes on the spike protein, but those directed against the highly immunogenic receptor-binding domain appear to have the greatest neutralizing potential, because they disrupt the interaction between the spike protein and the angiotensin II converting enzyme 2 receptor. Effector T cells destroy virus-infected cells. Macrophages phagocytose and digest antibody-tagged virus and virus-infected cells. Antigen-specific memory B and T cells develop to prevent future infection. In parallel with the serological response, antigen-specific memory B cells continuously acquire somatic mutations in their variable region genes to improve antigenic affinity. Upon antigenic re-exposure, memory B cells drive the recall response by differentiating into highaffinity antibody-secreting plasma cells. While antibody levels wane, antigen-specific memory B cells progressively become more numerous and mature. *An adequate response to vaccination can be defined as antibody levels above a certain antibody threshold 4 weeks after vaccination, e.g. 264 BAU/ml 38 . A low response can be defined by antibody levels >0 BAU/ml but <264 BAU/ml. These thresholds need to be redefined for Delta and Omicron. The benefit of primary prophylaxis against VOC has not been demonstrated.Tables J o u r n a l P r e -p r o o f 

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Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

Outcomes of patients with end-stage kidney disease hospitalized with COVID-19

A report from the Brescia Renal COVID Task Force on the clinical characteristics and short-term outcome of hemodialysis patients with SARS-CoV-2 infection

COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration

Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe

Factors associated with COVID-19-related death using OpenSAFELY

Chronic diseases, health conditions and risk of COVID-19-related hospitalization and in-hospital mortality during the first wave of the epidemic in France: a cohort study of 66 million people

COVID-19: clinical course and outcomes of 36 hemodialysis patients in Spain

Risk factors for severity of COVID-19 in chronic dialysis patients from a multicentre French cohort

Impact of first-wave COronaVIrus disease 2019 infection in patients on haemoDIALysis in Alsace: the observational COVIDIAL study

High Prevalence of Asymptomatic COVID-19 Infection in Hemodialysis Patients Detected Using Serologic Screening

The keys to control a COVID-19 outbreak in a haemodialysis unit

COVID-19 in Patients Undergoing Hemodialysis: Prevalence and Asymptomatic Screening During a Period of High Community Prevalence in a Large Paris Center

Serologic Detection of SARS-CoV-2 Infections in Hemodialysis Centers: A Multicenter Retrospective Study in Wuhan, China

COVID-19 Outbreak in an Urban Hemodialysis Unit

COVID-19 in Hospitalized Patients on Chronic Peritoneal Dialysis: A Case Series

COVID-19 in Peritoneal Dialysis Patients

SARS-CoV-2 in the peritoneal waste in a patient treated with peritoneal dialysis

Coronavirus disease 2019 (COVID-19) hospitalized patients with acute kidney injury treated with acute peritoneal dialysis do not have infectious peritoneal dialysis effluent

The biological and clinical significance of emerging SARS-CoV-2 variants

Outcomes From Infections With Variant Strains of SARS-CoV-2 Among Patients Receiving Maintenance Hemodialysis

Long covid-mechanisms, risk factors, and management

Long-term impact of COVID-19 among maintenance haemodialysis patients

Initial Effects of COVID-19 on Patients with ESKD

Excess Death Estimates in Patients with End-Stage Renal Disease -United States

Evaluation of Racial, Ethnic, and Socioeconomic Disparities in Initiation of Kidney Failure Treatment During the First 4 Months of the COVID-19 Pandemic

Changes in Treatment of Patients with Incident ESKD during the Novel Coronavirus Disease

COVID-19-Associated Decline in the Size of the End-Stage Kidney Disease Population in the United States

Impact of First Wave COVID-19 Crisis on Dialysis Parameters of COVID-Free Hemodialysis Patients: A NephoCare France Longitudinal Retrospective Cohort Study. Blood Purif

COVID-19 pandemic and worldwide organ transplantation: a population-based study

COVID-19 related mortality in kidney transplant and hemodialysis patients: a comparative, prospective registry based study. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc -Eur Ren Assoc

Panic in the Pandemic: When Should Kidney Transplant Programs Close?

Psychological Profiles of Chinese Patients With Hemodialysis During the Panic of Coronavirus Disease 2019. Front Psychiatry

2403 Establishment of the WHO International Standard and Reference Panel for anti-SARS-CoV-2 antibody

Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

Prolonged SARS-CoV-2 viral shedding in patients with chronic kidney disease. Nephrol Carlton Vic

Prolonged SARS-CoV-2 Viral RNA Shedding and IgG Antibody Response to SARS-CoV-2 in Patients on Hemodialysis

IgG Antibody Response to SARS-CoV-2 Infection and Viral RNA Persistence in Patients on Maintenance Hemodialysis

Can Testing Predict SARS-CoV-2 Infectivity? The Potential for Certain Methods To Be Surrogates for Replication-Competent Virus

Kinetics of Anti-SARS-CoV-2 IgG Antibodies in Hemodialysis Patients Six Months after Infection

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Hemodialysis Patients Make Long-Lived Antibodies against SARS-CoV-2 that May Be Associated with Reduced Reinfection

Neutralizing Antibody Responses After SARS-CoV-2 Infection in End-Stage Kidney Disease and Protection Against Reinfection

IgG SARS-CoV-2 Antibodies Persist at Least for 10 Months in Patients on Hemodialysis

SARS-CoV-2-reactive cellular and humoral immunity in hemodialysis population

Serial SARS-CoV-2 Receptor-Binding Domain Antibody Responses in Patients Receiving Dialysis

A Longitudinal, 3-Month Serologic Assessment of SARS-CoV-2 Infections in a Belgian Hemodialysis Facility

Longevity of SARS-CoV-2 immune responses in hemodialysis patients and protection against reinfection

Longevity and correlation with disease severity of the humoral and cellular response to SARS-CoV-2 infection in haemodialysis patients

T cell and antibody responses to SARS-CoV-2: Experience from a French transplantation and hemodialysis center during the COVID-19 pandemic

Antibody Status, Disease History, and Incidence of SARS-CoV-2 Infection Among Patients on Chronic Dialysis

Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers

Review of Early Immune Response to SARS-CoV-2 Vaccination Among Patients With CKD

Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine

Predictors and Dynamics of the Humoral and Cellular Immune Response to SARS-CoV-2 mRNA Vaccines in Hemodialysis Patients: A Multicenter Observational Study

The ROMANOV study found impaired humoral and cellular immune responses to SARS-CoV-2 mRNA vaccine in virus-unexposed patients receiving maintenance hemodialysis

Immunogenicity of SARS-CoV-2 Vaccine in Dialysis

Humoral and Cellular Responses to mRNA-1273 and BNT162b2 SARS-CoV-2 Vaccines Administered to Hemodialysis Patients

Humoral Response to mRNA versus an Adenovirus Vector-Based SARS-CoV-2 Vaccine in Dialysis Patients

Humoral Response to the Pfizer BNT162b2 Vaccine in Patients Undergoing Maintenance Hemodialysis

Experience with SARS-CoV-2 BNT162b2 mRNA vaccine in dialysis patients

Impaired humoral immunity to SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients and dialysis patients

Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis

Impaired humoral and cellular immunity after SARS-CoV-2 BNT162b2 (tozinameran) prime-boost vaccination in kidney transplant recipients

Haemodialysis patients show a highly diminished antibody response after COVID-19 mRNA vaccination compared with healthy controls

Short-term antibody response after 1 dose of BNT162b2 vaccine in patients receiving hemodialysis

Antibody Response to COVID-19 Vaccination in Patients Receiving Dialysis

Antibody response to mRNA SARS-CoV-2 vaccine among dialysis patients -a prospectivecohort study

Humoral response to BNT162b2 mRNA COVID-19 vaccine in peritoneal and hemodialysis patients: A comparative study

Safety and immediate humoral response of COVID-19 vaccines in chronic kidney disease patients: the SENCOVAC study

Longitudinal Humoral Responses after COVID-19 Vaccination in Peritoneal and Hemodialysis Patients over Twelve Weeks

Similar humoral immune responses in peritoneal dialysis and haemodialysis patients after two doses of the SARS-CoV-2 vaccine BNT162b2

Comparison of long-term antibody response to mRNA SARS-CoV-2 vaccine among peritoneal dialysis and hemodialysis patients

Humoral response after 3 doses of the BNT162b2 mRNA COVID-19 vaccine in patients on hemodialysis

COVID-19 vaccination in haemodialysis patients: good things come in threes…

SARS-CoV-2 Antibody Response After a Third Dose of the BNT162b2 Vaccine in Patients Receiving Maintenance Hemodialysis or Peritoneal Dialysis

High immunogenicity of a messenger RNAbased vaccine against SARS-CoV-2 in chronic dialysis patients

Humoral response to a third injection of BNT162b2 vaccine in patients on maintenance haemodialysis

Improved cellular and humoral immunity upon a second BNT162b2 and mRNA-1273 boost in prime-boost vaccination no/low responders with end-stage renal disease

A prospective observational study for justification, safety, and efficacy of a third dose of mRNA vaccine in patients receiving maintenance hemodialysis. Kidney Int

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7

Neutralizing antibodies against SARS-CoV-2 variants induced by natural infection or vaccination: a systematic review and pooled metaanalysis

1.617.2 and B.1.351 by BNT162b2 vaccination

A Meta-Analysis of Early Results to Predict Vaccine Efficacy against Omicron

Neutralizing antibody response against variants of concern after vaccination of dialysis patients with BNT162b2

Poor Neutralization and Rapid Decay of Antibodies to SARS-CoV-2 Variants in Vaccinated Dialysis Patients

Neutralising antibodies after COVID-19 vaccination in UK haemodialysis patients

Diminished and waning immunity to COVID-19 vaccination among hemodialysis patients in Israel: the case for a third vaccine dose

SARS-CoV-2 Vaccine Antibody Response and Breakthrough Infection in Dialysis

Seroresponse to SARS-CoV-2 Vaccines among Maintenance Dialysis Patients over Six Months

Waning humoral response 6 months after SARS-CoV-2 vaccination with the mRNA-BNT162b2 vaccine in hemodialysis patients: time for a boost

Long Term Humoral Immunity Decline in Hemodialysis Patients Following SARS-CoV-2 Vaccination

Cellular and humoral immunogenicity of a SARS-CoV-2 mRNA vaccine in patients on haemodialysis

Antibody and T Cell Response to SARS-CoV-2

Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients

Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273

Comparison of BNT162b2 (Pfizer-BioNtech) and mRNA-1273 (Moderna) SARS-CoV-2 mRNA vaccine immunogenicity in dialysis patients

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Seroprevalence of antibody to S1 spike protein following vaccination against COVID-19 in patients receiving hemodialysis: a call to arms

Real-World Effectiveness and Immunogenicity of BNT162b2 and mRNA-1273 SARS-CoV2 Vaccines in Patients on Hemodialysis

Vaccination and COVID-19 Dynamics in Hemodialysis Patients: A Population-Based Study in France

SARS-CoV-2 Vaccine Effectiveness and Breakthrough Infections in Maintenance Dialysis Patients

New analyses of two AZD7442 COVID-19 Phase III trials in high-risk populations confirm robust efficacy and long-term prevention

Variant SARS-CoV-2 MRNA Vaccines Confer Broad Neutralization as Primary or

Provide Update on Omicron Variant | Pfizer

to Evaluate Its COVID-19 Vaccine Against New Omicron COVID-19

Moderna Announces Preliminary Booster Data and Updates Strategy to Address Omicron Variant

Third BNT162b2 Vaccination Neutralization of SARS-CoV-2 Omicron Infection

Booster of MRNA-1273 Vaccine Reduces SARS-CoV-2 Omicron Escape from Neutralizing Antibodies

Pan-Sarbecovirus Neutralizing Antibodies in BNT162b2-Immunized SARS-CoV-1 Survivors

Trying to Block SARS-CoV-2 Transmission With Intranasal Vaccines

SARS-CoV-2 Vaccine Acceptability in Patients on Hemodialysis: A Nationwide Survey

Antihypertensive Drugs and COVID-19 Risk: A Cohort Study of 2 Million Hypertensive Patients. Hypertens Dallas Tex

Renin-Angiotensin Aldosterone System Inhibitors in Primary Prevention and COVID-19

A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19

Treatment impact on COVID-19 evolution in hemodialysis patients

Renin-Angiotensin System Blockers and the Risk of COVID-19-Related Mortality in Patients with Kidney Failure

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

How to recognize and manage COVID-19-associated coagulopathy

Arteriovenous fistulas thrombosis in hemodialysis patients with COVID-19

Dialysis circuit clotting in critically ill patients with COVID-19 infection

High Incidence of Circuit Clotting in Critically Ill COVID-19 Patients Treated with Renal Replacement Therapy

The management of dialysis access thrombosis during the COVID-19 pandemic

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Yngve Falck Ytter**COVID-19 Guideline, Part 1: Treatment and Management

The Exclusion of Patients with CKD in Prospectively Registered Interventional Trials for COVID-19-a Rapid Review of International Registry Data

Safety and efficacy of antivirals against SARS-CoV-2

Dexamethasone in Hospitalized Patients with Covid-19

Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

Remdesivir for the Treatment of Covid-19 -Final Report

Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Use of Remdesivir in Patients With COVID-19 on Hemodialysis: A Study of Safety and Tolerance

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19

Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19

SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19

Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study

Influence of treatment with neutralizing monoclonal antibodies on the SARS-CoV-2 nasopharyngeal load and quasispecies

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