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

NB and THW contributed equally.

https://doi.org/10.1016/j.kint.2021.03.032, Volume: 99, Issue: 6, Pages: 1489-1490

Article Type: Letter Article History

Publisher: International Society of Nephrology. Published by Elsevier Inc.

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Table of Contents

Supplementary Material

Anft,Blazquez-Navarro,Paniskaki,Skrzypczyk,Appel,Pfab,Uhle,Frahnert,Barenbrock,Büssemaker,Hörstrup,Doevelaar,Seibert,Hölzer,Stervbo,Dolff,Witzke,Babel,and Westhoff: SARS-CoV-2–reactive cellular and humoral immunity in hemodialysis population

To the editor:

The outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients receiving hemodialysis (HD) is significantly worse compared with the general population.1, 2, 3 Whether the SARS-CoV-2–specific immunity in patients with coronavirus disease 2019 (COVID-19) receiving dialysis is impaired as a possible cause for the inferior outcome is not known so far.

We performed an observational case-control study comparing the frequencies and functionality of SARS-CoV-2–reactive T cells as well as antibody titers in 14 COVID-19 convalescent patients receiving HD with 14 age-, sex-, and COVID-19–presentation matched patients with normal renal function (Supplementary Table S1).

In general, the frequencies of SARS-CoV-2 spike, nucleocapsid, and membrane protein-reactive T cells in patients receiving HD and patients with normal renal function were similar (Table 1 ; Supplementary Figure S1A). Spike-specific antibody titers were also comparable in both groups (Supplementary Figure S1B). Frequencies of SARS-CoV-2–reactive CD4⁺ and CD8⁺ T cells producing effector cytokines granzyme B, interleukin-2, tumor necrosis factor, and interferon-γ were similar or, for certain cytokines, even significantly higher in patients receiving HD compared with patients with normal renal function (Table 1; Supplementary Figure S1C). Patients receiving dialysis demonstrated higher frequencies of memory SARS-CoV-2–reactive T cells (Supplementary Figure S2).

Table 1

Frequency of SARS-CoV-2–reactive T cells in dialysis and nondialysis patients

Group, %	CD4⁺CD154⁺CD137⁺	CD4⁺CD154⁺CD137⁺
Group, %	CD4⁺CD154⁺CD137⁺	+Granzyme B⁺	+IFN-γ⁺	+IL-2⁺	+TNF⁺
Dialysis	0.7745 (0.057–1.57)	0.02029 (0–0.134)	0.1538 (0.017–0.437)	0.42 (0.054–0.651)	0.282 (0.02–0.588)
Nondialysis	0.237 (0.031–0.734)	0 (0–0.025)	0.0255 (0–0.195)	0.1165 (0.023–0.3)	0.0705 (0.012–0.223)

Group, %	CD8⁺CD137⁺	CD8⁺CD137⁺
Group, %	CD8⁺CD137⁺	+Granzyme B⁺	+IFN-γ⁺	+IL-2⁺	+TNF⁺
Dialysis	0.355 (0.187–1.21)	0.2795 (0.08–0.61)	0.0225 (0–0.1665)	0.0225 (0–0.096)	0.085 (0–0.15)
Nondialysis	0.1325 (0–0.33)	0.0205 (0–0.107)	0 (0–0.06)	0 (0–0.018)	0 (0–0.045)

IFN-γ, interferon-γ; IL-2, interleukin-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, tumor necrosis factor.

Frequency of SARS-CoV-2–reactive CD4⁺ or CD8⁺ T cells among all CD4⁺ or CD8⁺ T cells. Data are given as median (95% confidence interval).

To our knowledge, this exploratory study suggests for the first time that patients receiving dialysis are able to generate efficient T-cell immunity, as demonstrated by their multiple cytokine production. The magnitude and functionality of SARS-CoV-2–reactive T cells was comparable or even higher than in patients with normal renal function. Further larger studies are required to confirm our observation.

References

Seidel

, Holzer

, Appel

. Impact of renal disease and comorbidities on mortality in hemodialysis patients with COVID-19: a multicenter experience from Germany.

Jager

K.J.

, Kramer

, Chesnaye

N.C.

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

J.H.

, Hirsch

J.S.

, Wanchoo

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

see commentary on page 1275

Supplementary File (Word)

Supplementary Methods.:

Table S1.: Cohort characteristics.

Figure S1.: Frequency of SARS-CoV-2–reactive T cells. Isolated PBMCs from dialysis (n = 14) and nondialysis patients with normal renal function (n = 14) after a SARS-CoV-2 infection were stimulated for 16 hours with 1 μg/ml of SARS-CoV-2 OPPs from the M (n = 13/14), N (n = 13/14), or S (n = 14/14) protein. SARS-CoV-2–reactive T helper cells were identified as Life/Dead-Marker^–CD3⁺CD4⁺CD137⁺CD154⁺, and SARS-CoV-2–reactive cytotoxic T cells were identified as Life/Dead-Marker^–CD3⁺CD8⁺CD137⁺. (A) Frequencies of total SARS-CoV-2–reactive CD4⁺CD137⁺CD154⁺ and CD8⁺CD137⁺ T cells reactive to the M, N, or S protein combined are shown. (B) Comparison of the relative titers of SARS-CoV-2 Spike-protein–specific IgG antibodies of dialysis patients (n = 10) and nondialysis patients with normal renal function (n = 14), measured by ELISA and evaluated as the ratio to an internal control for samples with SARS-CoV-2–specific CD4⁺ T cells. (C) Identification of cytokine-expressing T cells reactive to the M, N, or S protein combined: expression of Th1 cytokines IFNγ, IL-2, or TNF and granzyme B among antigen-reactive CD4⁺CD137⁺CD154⁺ (upper panels) and CD8⁺CD137⁺ (lower panels) among all CD4⁺ or CD8⁺ cells, respectively. Groups were compared using a 2-sided, unpaired Mann–Whitney U test. P values ≤ 0.05 were defined as significant and are marked by an asterisk.

Figure S2.: SARS-CoV-2–reactive memory T-cell phenotypes. Isolated PBMCs from dialysis (n = 14) and nondialysis patients with normal renal function as the control (n = 14) with SARS-CoV-2 infection were stimulated for 16 hours with 1 μg/ml of SARS-CoV-2 OPPs from the M (n = 13/14), N (n = 13/14), or S (n = 14/14) protein. Presented are frequencies directed against all proteins combined. (A) Identification of antigen-reactive memory T cells: After gating on SARS-CoV-2–reactive CD4⁺CD137⁺CD154⁺ and CD8⁺CD137⁺ T cells, memory cells were identified by the expression of CD45RA and CCR7 as naïve (CD45RA⁺CCR7⁺), central-memory (CM, CD45RA^–CCR7⁺), effector-memory (EM, CD45RA^–CCR7^–), and TEMRA (CD45RA⁺CCR7^–) cells. Comparison of overall SARS-CoV-2–reactive naïve and memory (B) CD4⁺CD137⁺CD154⁺ and (C) CD8⁺CD137⁺ T cells. (D) Distribution of naïve and memory SARS-CoV-2–memory T-cell populations. Groups were compared using a 2-sided, unpaired Mann–Whitney U test. P values ≤ 0.05 are marked by an asterisk.