Key Points
Patients receiving hemodialysis (HD) have more inflammatory monocytes and less plasmacytoid dendritic cells (DCs) compared with healthy controls.
Patients on HD who have a poor antibody response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine had fewer monocyte-derived DCs and conventional DCs compared with good responders.
The defects in antigen presentation might be possible therapeutic targets to increase vaccine efficacy in HD patients.
Keywords: chronic kidney disease, basic science, COVID-19, dendritic cell, immune response, innate immunity, monocyte, mRNA vaccine, SARS-CoV-2
Introduction
Individuals receiving maintenance dialysis have markedly reduced survival compared with the general population, with a median survival of <4 years (1). Accounting for around 9% of all deaths, infections are the second leading cause of mortality in this population after cardiovascular diseases (1). The risk of sepsis-related mortality in patients undergoing dialysis is 30- to 50-fold higher than in controls (2), and risk of death from coronavirus disease 2019 (COVID-19) is similarly high (3).
Impaired immune responses may partially explain the propensity of patients on hemodialysis (HD) to severe infection, but the immune defects in patients on HD are still poorly understood. Patients receiving HD have been shown to have blunted immune responses to vaccines, such as those against hepatitis B, influenza (4,5), and, more recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (6,7). Although vaccination appears to confer patients on HD protection against infection and severe COVID-19 disease (8,9), vaccine effectiveness is lower than in healthy controls (HCs) (7). Furthermore, antibody levels decline more in patients on HD after the last dose compared with the healthy population, which might emphasize the need for booster doses in the dialysis population (9,10).
Previous studies have reported deficits in specific T- and B-cell responses after SARS-CoV-2 vaccination (11), but the underlying mechanisms causing these impairments are still poorly understood. Dendritic cells (DCs) are the major antigen-presenting cells (APCs) that bridge the innate and adaptive immune responses, and ESKD has a deleterious effect on these cells (reviewed in [12]), which include monocyte-derived DCs (MoDCs) (13) and plasmacytoid DCs (pDCs) (14). We thus hypothesized that impairments in DC number and function may underlie poor adaptive immune responses after SARS-CoV-2 vaccination in patients with ESKD receiving HD.
Material and Methods
Study Participants, Samples, Data Collection, and Ethics Approval
Since March 2020, we have been prospectively following in-center patients receiving HD at seven centers in the Quebec Renal Network COVID-19 study for incidence and outcomes related to COVID-19, as previously described (6). Consenting adult patients receiving in-center HD treatments at four different hospitals in Montreal were enrolled in this substudy (n=51). We collected plasma before and 4 weeks after the first dose of either BNT162b2 or mRNA-1273 SARS-CoV-2 vaccine, between January and June 2021. PBMCs were collected at different time points regarding vaccination. Demographic and clinical data were obtained and recorded in the Research Electronic Data Capture tool (REDCap, version 9.1.15). We concurrently obtained PBMCs from HCs without any major comorbidities that consented to give blood between June and December 2021, regardless of their vaccination status. Informed consent was obtained, and the institutional review board of each institution approved this study (Centre Hospitalier de l'Université de Montréal, Hôpital Maisonneuve-Rosemont, Hôpital du Sacré-Coeur de Montréal and McGill University Health Centre), in agreement with the Declaration of Helsinki. Race and ethnicity were not reported.
Antibody Measurements
To assess humoral immune response to the vaccine, we used an ELISA to measure the IgG antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein in thawed plasma, as previously described (6,15). Anti-RBD IgG levels were reported as relative light units (RLUs) normalized to CR3022 mAb, a commercially available mAb against the RBD of the SARS-CoV-2 S glycoprotein. BSA and CR3022 were used as negative and positive controls, respectively. We previously showed that the 25th percentile anti-RBD IgG level in vaccinated health care workers after one dose of BNT162b2 was 14 RLU, and was 18 RLU in convalescent plasma from patients on HD who were unvaccinated and survived COVID-19 (6). On the basis of these data, we conservatively defined “responders” and “nonresponders” as having an anti-RBD IgG level >10 or ≤10 RLU, respectively, 4 weeks after the first vaccine dose.
PBMC Isolation and Culture
PBMCs were isolated using a standard gradient separation medium and cryopreserved in 10% DMSO and 90% FCS. Monocytes were isolated by plastic adherence and differentiated into DCs in X-Vivo (Lonza), 5% human serum, 1% penicillin-streptomycin, 1% GlutaMAX, and 1-mM sodium pyruvate and supplemented with GM-CSF (800 IU/ml; Miltenyi) and IL-4 (1000 IU/ml; Miltenyi) over 5 days. Culture media was changed on day 3. Cells were then matured for 2 days in the same media with the addition of GM-CSF, IL-4, TNF-α (10 ng/ml; Miltenyi), IL-1β (10 ng/ml; Peprotech), IL-6 (100 ng/ml; Shenandoah), and PGE2 (1 μg/ml; Peprotech). IFN-γ (1000 U/ml; Peprotech) was added on the sixth day of the culture for the final 24 hours of the maturation step.
Flow Cytometry
Cells were stained with fixable viability dye (65-0865-18; Thermo Fisher Scientific) and surface markers in PBS for 30 minutes at 4°C. Samples were analyzed on a BD LSRFortessa X-20 and results were analyzed using FlowJo Software version 10.7.1. We used the following antibodies from Biolegend: HLA-DR (L234), CD1c (L161), CD14 (63D3), CD86 (BU63), CD11c (3.9), CD123 (6H6), CD206 (15-2), CD141 (M80), and CD80 (2D10). We also used the following antibodies from BD Biosciences: CD33 (P67.7) and CD16 (3G8). To evaluate the functional ability of moDCs for micropinocytosis, 0.25×105 moDCs were incubated with FITC-labeled albumin (50 μg/ml; Sigma) for 1 hour at 4°C (control) or 37°C.
Statistical Analysis
Descriptive characteristics are reported as proportions or means with SDs, as appropriate. Continuous nonparametric outcomes were compared using Mann–Whitney U tests. Two-sided α P value of <0.05 was considered significant. All statistics were performed in Prism version 9.3.1.
Results
Myeloid Cell Profile in Patients on Hemodialysis Compared with HCs
To better understand the effect of uremia and HD on innate immune cells, we first analyzed data from 12 HCs and 51 patients on HD, regardless of their vaccine status. Their baseline characteristics are provided in Table 1. The frequency of three monocyte subtypes (classic, nonclassic, and intermediate), pDC, and conventional DC type 1 (cDC1) and cDC2 were determined by flow cytometry (Supplemental Figure 1). Compared with HCs, patients on HD had more nonclassic and intermediate monocytes (Figure 1A) and less pDCs (Figure 1B), but a similar percentage of classic monocytes (Figure 1A), cDC1 and cDC2 (Figure 1B).
Table 1.
Patient characteristics
| Variable | Controls (n=12) | Patients on Hemodialysis (n=51)a | Patients on Hemodialysis, Excluding Patients with Previous COVID-19 Infection | |
|---|---|---|---|---|
| Patients that Responded to First mRNA Vaccine Dose (n=9) | Patients that Did Not Respond to First mRNA Vaccine Dose (n=34) | |||
| Age (yr), mean±SD (median, range) | 52±17.1 (55, 31–82) | 62±14.9 (64, 31–85) | 57±14.6 (62, 31–79) | 63±14.5 (66, 34–85) |
| Men, n (%) | 7 (58) | 31 (61) | 6 (67) | 22 (65) |
| Duration of hemodialysis (yr), mean±SD (median, range) | N/A | 5.7±5.6 (3.9, 0.2–28.4) | 9.7±7.5 (8.5, 0.5–23.4) | 5.1±5.2 (3.8, 0.2–28.4) |
| Immunosuppressive medications, n (%) | 0 | 8 (16) | 4 (44) | 4 (12) |
| Diabetes, n (%) | 0 | 24 (47) | 4 (44) | 16 (47) |
| Cancer, n (%) | 0 | 3 (6) | 0 | 3 (9) |
COVID-19, coronavirus disease 2019; N/A, not applicable.
Used in Figure 1.
Figure 1.
Hemodialysis (HD) patients have different innate cell profile compared with healthy controls (HCs). PBMCs from 12 HCs and 51 patients on HD were analyzed, regardless of their severe acute respiratory syndrome coronavirus 2 vaccination status. (A) Comparison of the frequency of classic, nonclassic, and intermediate monocytes, as determined by their expression of CD14 and CD16, between HCs and patients on HD. Representative flow cytometry plots of the monocytes in HCs and patients on HD (left). Percentages represent the percent of live cells. Summarized data on the right. (B) Comparison between the frequency of plasmacytoid dentritic cells (pDCs) and conventional DCs type 1 (cDC1s) and cDC2s among live cells in HCs and patients on HD. (C) Schematic representation of the cell culture to obtain mature monocyte-derived DCs (moDCs). Monocytes were differentiated into DCs in 5 days and then matured in 2 days. (D) Percentage of moDCs obtained after 7 days of culture per plated PBMCs in patients on HD and HCs. (E) Expression levels of HLA-DR, CD80, and CD86 in moDCs (gated on live CD11c+CD206+) obtained after 7 days of culture in HCs versus patients on HD. (F) One representative histogram of the macropinocytosis assay. On the left, one representative histogram showing FITC-labeled albumin uptake at 4°C as the negative control, the maximum uptake in immature moDCs (day 5, white), and the downregulation after maturation (dark gray). On the right, comparison of the percentage of FITC-Hi moDCs derived from the monocytes of HCs or patients on HD. Mann–Whitney U tests comparing HCs and patients on HD. Mean±SD. *P≤0.05, **P≤0.01, ****P≤0.0001.
Because moDCs have important antigen-presenting functions, the ability of the monocytes of patients on HD and HCs to differentiate into mature DCs in vitro was evaluated (Figure 1C). The maturation status of these cells was first established on the basis of their expression of the costimulation molecules CD80 and CD86 and the antigen-presenting molecule HLA-DR. Despite the observed differences in monocytes subtypes, there were no significant differences between the percentage of mature moDCs per PBMCs (Figure 1D) or their expression of HLA-DR, CD80, and CD86 (Figure 1E) in patients on HD compared with HCs. During maturation, moDCs lose their ability to uptake albumin via macropinocytosis. Therefore, determination of the albumin uptake can also be used to monitor terminal differentiation (16). Interestingly, mature moDCs from patients on HD showed a greater uptake of the FITC-labeled albumin when compared with HCs, suggesting an impaired maturation (Figure 1F).
Innate Immune Responses in Responders versus Nonresponders on HD to the First Dose of mRNA SARS-CoV-2 Vaccine
To investigate whether the differences seen in patients on HD were associated with the IgG response after one dose of mRNA SARS-CoV-2 vaccine, we then compared the innate immune phenotype of patients on HD who were responders to those that were nonresponders. Eight of 51 (16%) patients on HD had a positive baseline anti-RBD IgG or a history of COVID-19 infection and were thus excluded from comparison between responders and nonresponders. Of the 43 remaining, nine patients (21%) had an anti-RBD IgG RLU of ≥10, which we defined as responders, as previously described (6).
We did not identify any differences between responders and nonresponders in the frequency of the three different monocyte subtypes; i.e., classic, intermediate, and nonclassic (Figure 2A). The frequency of pDCs was also similar between the two groups (Figure 2B). However, nonresponders had significantly fewer cDC1s and cDC2s (Figure 2C). Finally, nonresponders had significantly fewer moDCs after a 7-day culture compared with responders (Figure 2C). However, the obtained moDCs expressed similar levels of CD80, CD86, and HLA-DR (Figure 2D). We also evaluated the macropinocytosis ability of the moDCs obtained after 7 days of culture and responders and nonresponders were similar (Figure 2E). Linear regression analysis also confirmed the correlation between the percentage of cDC1s and percentage of moDCs to the anti-RBD IgGs 4 weeks after the first dose (Supplemental Figure 2).
Figure 2.
HD patients that were nonresponders to first dose of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine have different antigen-presenting cell populations compared to responders. Anti-RBD IgG ELISAs were done in serum of patients on HD who did not previously have coronavirus disease 2019 4 weeks after the first dose of the SARS-CoV-2 mRNA vaccine. Patients with ≥10 RLU were considered responders (R), and those with a titer of <10 RLU were considered as nonresponders (NR). We compared in the frequency between Rs and NRs of (A) classic, nonclassic, and intermediate monocytes; and (B) pDCs, cDC1s, and cDC2s. (C) Percentage of moDCs obtained after 7 days (D7) of culture in Rs and NRs. (D) Expression levels of HLA-DR, CD80, and CD86 on moDCs (gated on live CD11c+CD206+) in Rs versus NRs. (E) Macropinocytosis ability of moDCs as assessed by the percentage of moDCs expressing high (HI) levels of FITC-labeled albumin in Rs versus NRs. Mann–Whitney U tests comparing Rs with NRs. Mean±SD. *P≤0.05, **P≤0.01, ***P≤0.005.
Discussion
In this study, we found patients on HD had more inflammatory monocytes compared with HCs, but there were no identifiable differences in classic monocytes, similarly to previous studies (17). This inflammatory phenotype could affect the differentiation of monocytes into moDCs and their role as APCs in vaccination. MoDCs are mostly derived from classic monocytes, and frequencies of this subpopulation of monocytes were similar between patients on HD and HCs. This might explain why we did not observe any differences in the number of moDCs obtained. However, moDCs from patients on HD did not lose the ability for macropinocytosis, which might point toward an impairment in terminal differentiation and confirm the results of other studies (16). ESKD is also associated with a decrease in circulating DCs, mostly attributed to the pDC population (12). Our results corroborate this observation, although patients on HD and HCs were not age and sex matched.
We then focused on patients on HD and evaluated the association between their levels of anti-RBD–elicited antibodies upon the first dose of a mRNA SARS-CoV-2 vaccine and the innate immune composition of the peripheral blood. We found an association between the myeloid DC subtypes, cDC1 and cDC2, but not with pDCs. These results are in line with the fact that cDC1s and cDC2s are potent APCs, with the former being able to efficiently crosspresent antigens on MHC class I molecules, and the latter being able to present antigens on MHC class II molecules. pDCs are weaker APCs in contrast to cDCs, thus they might have a minor role in vaccine response. moDCs are also potent APCs and the immune response to hepatitis B virus vaccination is, at least partially, related to their dysfunction (16). Similarly, in our study, vaccine nonresponders had fewer moDCs, emphasizing the role of APCs in vaccine response.
This is the first study addressing the role of monocytes and DCs in response to SARS-CoV-2 vaccination in patients on HD. A limitation of this study is that HCs were not age and sex matched with patients on HD, and the latter had a tendency of being older (P=0.37, two tailed-test). Another limitation is that the association between components of the innate immune system and the humoral response to SARS-CoV-2 vaccine was evaluated only in patients on HD, limiting generalizability to the general population. PBMCs were also collected at different time points regarding vaccination. Such variability in PBMC measurements might limit the generalizability of the observed phenotype to every time point. However, the populations studied are quite stable over time, except in the days after vaccination (18). Finally, due to the limited number of patients in this study and the descriptive nature of our work, the results are of a hypothesis-generating nature.
In conclusion, because DCs are potent APCs, the defect in DC immunity in vaccine nonresponders might be associated with the observed impairment in IgG elicitation after the first dose of mRNA SARS-CoV-2 vaccine. However, the causal relationship between the observed defect in DC immunity and humoral response remains to be proven. The use of adjuvants that can activate DCs, such as GM-CSF, levamisole, or HB-AS04/AS02, have been proposed to improve seroconversion to hepatitis B in patients on HD (12). On the basis of our results, we could hypothesize such adjuvants might also improve the immune response to SARS-CoV-2 vaccine in patients on HD. Another way to improve seroconversion is to give multiple vaccine doses, emphasizing the need to adapt vaccination strategies to this population.
Disclosures
A. Finzi reports receiving research funding and honoraria from, and serving in an advisory or leadership role for, ViiV. C. Lamarche reports having the patents PCT/CA2018/051167 and PCT/CA2018/051174 filed. R.S. Suri reports receiving honoraria from Amgen and Otskuka; and serving in an advisory or leadership role for Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health and Canadian Society of Nephrology. All remaining authors have nothing to disclose.
Funding
This work was supported by Gouvernement du Canada Canadian Institutes of Health Research (CIHR) grant 447760 to R.S. Suri and C. Lamarche, le Ministère de l’Économie et de l’Innovation du Québec Programme de soutien aux organismes de recherche et d’innovation to A. Finzi; and the Fondation du CHUM. This work was also supported by CIHR foundation grant 352417 to A. Finzi, operating Pandemic and Health Emergencies Research grant 177958 to A. Finzi, and operating grant 178344 to D.E. Kaufmann and A. Finzi; and the Canada Foundation for Innovation Exceptional Opportunities Fund for COVID-19 grant 41027 to A. Finzi and D.E. Kaufmann.
Acknowledgments
The authors thank the participants for donating their blood samples. We are grateful to our research coordinators, Ms. Norka Rios, Ms. Marie-Line Caron, Ms. Guylaine Marcotte, Ms. Karine Chaussé, Ms. Samantha Parsons, Ms. Nathalie Brassard, and Mélanie Laporte. We thank Dr. Nick Bertos and the Research Institute of the McGill University Health Center for sample processing and storage.
This work is submitted by the authors on behalf of the COVID-19 Study Team of the Réseau rénal québécois.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author Contributions
A. Finzi, G. Goyette, D.E. Kaufmann, C. Lamarche, L. Marchitto, M. Raymond, and R.S. Suri reviewed and edited the manuscript; A. Finzi, D.E. Kaufmann, C. Lamarche, and R.S. Suri were responsible for funding acquisition and resources; G. Goyette was responsible for investigation; D.E. Kaufmann, C. Lamarche, M. Raymond, and N. Valentini conceptualized the study; C. Lamarche provided supervision and was responsible for project administration; C. Lamarche, M. Raymond, and N. Valentini were responsible for methodology; L. Marchitto and N. Valentini were responsible for data curation; and N. Valentini wrote the original draft and was responsible for formal analysis.
Data Sharing Statement
Partial restrictions to the data and/or materials apply. Data available upon request to the corresponding author.
Supplemental Materials
This article contains the following supplemental material online at http://kidney360.asnjournals.org/lookup/suppl/doi:10.34067/KID.0002542022/-/DCSupplemental.
Flow cytometry gating strategy. Download Supplemental Figure 1, PDF file, 408 KB (407.4KB, pdf) .
Comparison between different thresholds of anti-RBD IgG ELISAs to define the responders. Download Supplemental Figure 2, PDF file, 408 KB (407.4KB, pdf) .
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Flow cytometry gating strategy. Download Supplemental Figure 1, PDF file, 408 KB (407.4KB, pdf) .
Comparison between different thresholds of anti-RBD IgG ELISAs to define the responders. Download Supplemental Figure 2, PDF file, 408 KB (407.4KB, pdf) .