www.kidney-international.

org letters to the editor

Gross hematuria following their patients with glomerular disease after SAR2-CoV-2
vaccination to determine the frequency and consequences of
vaccination for severe acute vaccine-induced disease activation.
respiratory syndrome coronavirus 1. Pardi N, Hogan MJ, Naradikian MS, et al. Nucleoside-modified mRNA
vaccines induce potent T follicular helper and germinal center B cell
2 in 2 patients with IgA responses. J Exp Med. 2018;215:1571–1588.
2. van den Wall Bake AW, Beyer WE, Evers-Schouten JH, et al. Humoral
nephropathy immune response to influenza vaccination in patients with primary
immunoglobulin A nephropathy: an analysis of isotype distribution and
size of the influenza-specific antibodies. J Clin Invest. 1989;84:1070–1075.
see commentary on page 1275
Lavinia Negrea1 and Brad H. Rovin2
1
To the editor: Several of the severe acute respiratory syn- Department of Internal Medicine, Division of Nephrology, University Hospital
drome coronavirus 2 (SARS-CoV-2) vaccines use a nucleoside- Cleveland Medical Center, Case Western Reserve University, Cleveland, Ohio,
USA; and 2Department of Internal Medicine, Division of Nephrology, The Ohio
modified, purified mRNA lipid nanoparticle-encapsulated
State University Wexner Medical Center, Columbus, Ohio, USA
platform. Compared with traditional inactivated viral and
adjuvanted protein vaccines, this RNA platform elicits far Correspondence: Brad H. Rovin, Nephrology Division, The Ohio State Uni-
versity Wexner Medical Center, 1664 Neil Ave, Fourth Floor, Columbus, Ohio
higher neutralizing antibody titers, stronger antigen-specific 43201, USA. E-mail: brad.rovin@osumc.edu
cluster of differentiation (CD) 4þ and CD8þ T-cell re-
Kidney International (2021) 99, 1487; https://doi.org/10.1016/j.kint.2021.03.002
sponses, and stronger germinal center B and TFH cell activation
Copyright ª 2021, International Society of Nephrology. Published by
in experimental animals.1 The activated CD4þ and CD8þ T Elsevier Inc. All rights reserved.
cells produce several proinflammatory cytokines, including
interferon-g and tumor necrosis factor-a. This led us to
wonder if these vaccines may activate or exacerbate immune- Weak anti–SARS-CoV-2
mediated glomerular diseases. Two individuals with biopsy-
proven IgA nephropathy (IgAN) developed gross hematuria antibody response after the
shortly following the second dose of the Moderna vaccine. The first injection of an mRNA
patients are described in Table 1. At baseline, both had pro-
teinuria of <1 g/d and well-preserved kidney function. Several COVID-19 vaccine in kidney
hours after the second dose of vaccine was given, both devel- transplant recipients
oped systemic symptoms, ranging from body aches, headache,
and fatigue to fever and chills. Between 8 and 24 hours after see commentary on page 1275
systemic symptoms appeared, the patients noticed gross he-
To the editor: International recommendations on corona-
maturia that resolved after 3 days. Serum creatinine did not
virus disease 2019 (COVID-19) vaccine distribution have
increase, but proteinuria increased in 1 patient (Table 1).
given priority to immunocompromised patients, including
Although we did not expect an exacerbation of IgAN after a
kidney transplant recipients (KTRs).1,2 Unfortunately, this
nonmucosal immune challenge, IgAN patients have previously
guidance has been released without inclusion of this clinical
been reported to have a stronger IgA1 (albeit monomeric)
population in vaccine clinical trials. In an effort to shed light
response to intramuscular influenza vaccine than healthy
on the efficacy and safety of an mRNA COVID-19 vaccine in
subjects.2 These episodes of apparent IgAN exacerbation
KTRs, this preliminary study was undertaken to investigate
should prompt the nephrology community to closely follow

Table 1 | Patient demographics and clinical characteristics

Gross hematuria Persistent Proteinuria between Proteinuria 3 weeks after
Patient Age, Year IgAN events during microscopic Proteinuria SARS-Cov-2 vaccine last SARS-CoV-2 vaccine
no. yr Sex Race diagnosed Treatment disease course hematuria in 2020, g/d doses, g/d dose, g/d
1 38 F W 2005 RAASi At presentation; Yes 0.63 0.82 1.40
during 1 episode of
gastroenteritis;
occasionally after
yearly influenza
vaccine
2 38 F W 2019 Cyc þ Pred At presentation only Yes 0.43 0.59 0.40
(6 mo), then
RAASi
Cyc, cyclophosphamide; F, female; IgAN, IgA nephropathy; Pred, prednisone; RAASi, renin-angiotensin-aldosterone system inhibitor; SARS-CoV-2, severe acute respiratory
syndrome coronavirus 2; W, white.

Kidney International (2021) 99, 1487–1501 1487

letters to the editor

University Hospital (Strasbourg, France) between January 21

and 28, 2021. All had a negative history for COVID-19 and
tested negative for anti–SARS-CoV-2 antibodies on the day of
the first injection. The anti–SARS-CoV-2 antibody response
against the spike protein was assessed at 28 days after injection
using the ARCHITECT IgG II Quant test (Abbott, Abbott Park,
IL), with titers >50 arbitrary units (AUs)/ml being considered
as positive (detection range, 6.8–40,000 AUs/ml; positive
agreement, 99.4%; negative agreement, 99.6%).
One patient developed mild symptomatic COVID-19 7
days after injection, and only 26 (10.8%) KTRs had a positive
serology at 28 days after injection. The median IgG titer was
224 AUs/ml (interquartile range, 76496 AUs/ml), whereas
the median IgG titer in the seronegative group was <6.8 AUs/
ml (Figure 1). Patients who seroconverted had longer time
from transplantation, received less immunosuppression, and
Figure 1 | Anti-spike IgG antibody titers measured at 28 days had a better kidney function (Table 1).
after vaccination in 215 seronegative kidney transplant
recipients (median titer, <6.8 arbitrary units [AUs]/ml
In summary, the burden of immunosuppression may
[interquartile range, <6.8L<6.8 AUs/ml]) and 26 seropositive induce a weak anti–SARS-CoV-2 antibody response in KTRs
kidney transplant recipients (median titer, 224 AUs/ml after the first injection of an mRNA COVID-19 vaccine. This
[interquartile range, 76L496 AUs/ml]). The dotted line indicates finding is strikingly different compared with immunocom-
the cutoff for positivity (50 AUs/ml).
petent subjects, who invariably seroconverted after the first
the anti–severe acute respiratory syndrome coronavirus 2 injection.3,4 We highlight the need not to delay the second
(SARS-CoV-2) antibody response after the first injection. vaccine injection in immunocompromised patients. Close
We examined 242 KTRs who received the first injection of surveillance is also recommended to discuss the opportunity
the Moderna mRNA-1273 vaccine (100 mg) at the Strasbourg of a third dose in less responsive patients.
Table 1 | Characteristics of kidney transplant recipients, according to serologic response after the first dose of the Moderna
mRNA-1273 vaccine
SARS-CoV-2 SARS-CoV-2
Entire cohort seronegative seropositive Missing
Characteristics (n[241)a patients (n[215) patients (n[26) P value data

Age, yr 57.7 (49.3–67.6) 57.7 (49.6–67.7) 58.4 (43.3–66.9) 0.51 0

Male sex 156 (64.7) 142 (66.1) 14 (53.9) 0.28 0
BMI, kg/m2 25.7 (22.6–29.5) 25.7 (22.8–29.4) 26.4 (21.9–29.9) 0.73 2
Time from kidney transplantation, yr 6.4 (2.9–13) 5.8 (2.8–11.9) 15.4 (8.6–25.9) <0.001 2
First transplantation 202 (83.8) 176 (81.8) 26 (100) 0.01 0
Deceased donor 192 (79.6) 172 (80) 20 (76.9) 0.8 0
ABO group 0.02 2
O 94 (39.3) 82 (38.5) 12 (46.2)
A 101 (42.3) 93 (43.7) 8 (30.8)
B 30 (12.6) 29 (13.6) 1 (3.9)
AB 14 (5.9) 9 (4.2) 5 (19.2)
Induction treatment 0.001 7
Anti-thymocyte globulin 138 (59.5) 127 (60.8) 11 (47.8) 9
Anti-CD25 88 (37.9) 80 (38.3) 8 (34.8)
No induction 6 (2.6) 2 (1) 4 (17.4)
CNI 0.06 0
Tacrolimus 133 (55.2) 124 (57.7) 9 (34.6)
Ciclosporin 82 (34) 69 (32.1) 14 (50)
No CNI 26 (10.8) 22 (10.2) 4 (15.4)
MMF/MPA 191 (79.3) 177 (82.3) 14 (53.9) 0.002 0
Azathioprine 7 (2.9) 4 (1.86) 3 (11.5) 0.03 0
mTOR inhibitors 35 (14.5) 32 (14.9) 3 (11.6) 1 0
Steroids 142 (58.9) 133 (61.9) 9 (34.6) 0.01 0
Belatacept 9 (3.8) 9 (4.2) 0 0.26 0
eGFR, ml/min per 1.73 m2 51.6 (38.1–68) 51 (37.9–66.5) 64.9 (39.9–72.2) 0.08 0
Serum creatinine, mmol/L 118 (99–158) 120 (101–159) 104 (85–134) 0.05 0
BMI, body mass index; CD, cluster of differentiation; CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; MMF, mycophenolate mofetil; MPA, mycophenolic
acid; mTOR, mechanistic target of rapamycin; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
a
The patient who developed coronavirus disease 2019 after the first injection was excluded from the analysis.
Continuous variables are presented as medians (interquartile ranges), whereas categorical variables are given as n (%).

1488 Kidney International (2021) 99, 1487–1501

 letters to the editor

1. Centers for Disease Control and Prevention. COVID-19 vaccination program We performed an observational case-control study
operational guidance. Available at: https://www.cdc.gov/vaccines/covid-19/
covid19-vaccination-guidance.html. Accessed March 1, 2021.
comparing the frequencies and functionality of SARS-CoV-2–
2. ECD. COVID-19 vaccination and prioritisation strategies in the EU/EEA. reactive T cells as well as antibody titers in 14 COVID-19
Available at: https://www.ecdc.europa.eu/sites/default/files/documents/ convalescent patients receiving HD with 14 age-, sex-, and
COVID-19-vaccination-and-prioritisation-strategies.pdf. Accessed March 1, COVID-19–presentation matched patients with normal renal
2021.
3. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine function (Supplementary Table S1).
against SARS-CoV-2 — preliminary report. N Engl J Med. 2020;383:1920– In general, the frequencies of SARS-CoV-2 spike,
1931. nucleocapsid, and membrane protein-reactive T cells in
4. Prendecki M, Clarke C, Brown J, et al. Effect of previous SARS-CoV-2
infection on humoral and T-cell responses to single-dose BNT162b2 patients receiving HD and patients with normal renal
vaccine. Lancet. 2021;397:1178–1181. function were similar (Table 1; Supplementary Figure S1A).
Spike-specific antibody titers were also comparable in both
Ilies Benotmane1,2, Gabriela Gautier-Vargas1, groups (Supplementary Figure S1B). Frequencies of SARS-
Noëlle Cognard1, Jérôme Olagne1, CoV-2–reactive CD4þ and CD8þ T cells producing effector
Françoise Heibel1, Laura Braun-Parvez1, cytokines granzyme B, interleukin-2, tumor necrosis factor,
Jonas Martzloff1, Peggy Perrin1, Bruno Moulin1,2, and interferon-g were similar or, for certain cytokines, even
significantly higher in patients receiving HD compared with
Samira Fafi-Kremer2,3 and Sophie Caillard1,2 patients with normal renal function (Table 1; Supplemen-
1
Department of Nephrology and Transplantation, University Hospital, Stras-
bourg, France, 2Inserm UMR S1109, LabEx Transplantex, Fédération de tary Figure S1C). Patients receiving dialysis demonstrated
Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, higher frequencies of memory SARS-CoV-2–reactive T cells
Strasbourg, France; and 3Department of Virology, University Hospital, Stras- (Supplementary Figure S2).
bourg, France To our knowledge, this exploratory study suggests for
Correspondence: Ilies Benotmane, Department of Nephrology and Trans- the first time that patients receiving dialysis are able to
plantation, Strasbourg University Hospital, 1 Place de l’Hopital, 67091 generate efficient T-cell immunity, as demonstrated by
Strasbourg, Cedex, France. E-mail: Ilies.benotmane@chru-strasbourg.fr their multiple cytokine production. The magnitude and
Kidney International (2021) 99, 1487–1489; https://doi.org/10.1016/ functionality of SARS-CoV-2–reactive T cells was compa-
j.kint.2021.03.014 rable or even higher than in patients with normal renal
Copyright ª 2021, International Society of Nephrology. Published by
function. Further larger studies are required to confirm our
Elsevier Inc. All rights reserved.
observation.

SARS-CoV-2–reactive cellular SUPPLEMENTARY MATERIAL

and humoral immunity in Supplementary File (Word)
Supplementary Methods.
hemodialysis population Table S1. Cohort characteristics.
Figure S1. Frequency of SARS-CoV-2–reactive T cells. Isolated PBMCs
see commentary on page 1275 from dialysis (n ¼ 14) and nondialysis patients with normal renal
function (n ¼ 14) after a SARS-CoV-2 infection were stimulated for 16
To the editor: The outcome of severe acute respiratory hours with 1 mg/ml of SARS-CoV-2 OPPs from the M (n ¼ 13/14), N
syndrome coronavirus 2 (SARS-CoV-2) infection in patients (n ¼ 13/14), or S (n ¼ 14/14) protein. SARS-CoV-2–reactive T helper
cells were identified as Life/Dead-Marker–CD3þCD4þCD137þCD154þ,
receiving hemodialysis (HD) is significantly worse compared
and SARS-CoV-2–reactive cytotoxic T cells were identified as Life/
with the general population.1–3 Whether the SARS-CoV-2– Dead-Marker–CD3þCD8þCD137þ. (A) Frequencies of total SARS-CoV-
specific immunity in patients with coronavirus disease 2019 2–reactive CD4þCD137þCD154þ and CD8þCD137þ T cells reactive to
(COVID-19) receiving dialysis is impaired as a possible cause the M, N, or S protein combined are shown. (B) Comparison of the
for the inferior outcome is not known so far. relative titers of SARS-CoV-2 Spike-protein–specific IgG antibodies of

Table 1 | Frequency of SARS-CoV-2–reactive T cells in dialysis and nondialysis patients

CD4DCD154DCD137D
Group, % D
CD4 CD154 CD137D D
DGranzyme B D
DIFN-gD DIL-2D DTNFD
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)

CD8DCD137D
Group, % D
CD8 CD137 D
DGranzyme B D
DIFN-g D
DIL-2D DTNFD
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-g, interferon-g; IL-2, interleukin-2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNF, tumor necrosis factor.
Frequency of SARS-CoV-2–reactive CD4þ or CD8þ T cells among all CD4þ or CD8þ T cells. Data are given as median (95% confidence interval).

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