# De novo posttransplant membranous nephropathy following BNT162b2 mRNA COVID-19 vaccine in a kidney transplant recipient

Nathalie Chavarot, Michael Padden, Lucile Amrouche, Stéphanie Malard, Anne Scemla, Rebecca Sberro-Soussan, Juliette Léon, Christophe Legendre, Jean Paul Duong, Julien Zuber, et al.

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Nathalie Chavarot, Michael Padden, Lucile Amrouche, Stéphanie Malard, Anne Scemla, et al. De novo posttransplant membranous nephropathy following BNT162b2 mRNA COVID-19 vaccine in a kidney transplant recipient. American Journal of Transplantation, 2022, 22 (12), pp.3188-3189. 10.1111/ajt.17166. hal-04052551

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# De novo posttransplant membranous nephropathy following BNT162b2 mRNA COVID-19 vaccine in a kidney transplant recipient

*To the Editor:*

Mass COVID-19 vaccination programs in kidney transplant patients (KTRs) have demonstrated an excellent safety profile, without increased rates of ensuing alloimmune events. However, autoimmune diseases may seldom occur after vaccination. We report the case of a KTR who presented de novo posttransplant membranous nephropathy (MN) following administration of COVID-19 vaccine.

A 66-year-old patient underwent first kidney transplantation for autosomal-dominant polycystic-kidney-disease-related end-stage kidney disease in June 2020. His medical history included hypertension and left nephrectomy in 2016. After basiliximab induction, the maintenance regimen consisted of tacrolimus, mycophenolic acid, and steroids. His baseline creatinine level was 100µmol/L, and he remained free of proteinuria during the posttransplant course. A 3-month protocol graft biopsy was unremarkable. Immunohistochemistry (IHC) C4d staining was negative (Figure 1A,B).

The patient received the second injection of the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) in March 2021.

Subsequent serology tests showed negative results, consistent with a blunted antibody response to the vaccine, as widely reported in KTRs.

Eight weeks after the second vaccine dose, the patient underwent a 1-year protocol graft biopsy. Concurrent creatinine level and proteinuria were 120 µmol/L and negative, respectively. Light microscopy showed normal glomeruli and ruled out subclinical rejection(Figure 1D). However, C4d staining revealed the presence of granular staining along the glomerular basement membrane consistent with stage 1 MN (Figure 1E). Anti-phospholipase-A2-receptor (PLA2R) immunochemistry analysis showed strong positive staining on the glomerular capillary walls (Figure 1F). Circulating PLA2R antibodies were negative. Notably, IHC staining for PLA2R and C4d was retrospectively negative in the 3-month protocol graft biopsy (Figure 1E) and in the native kidney specimen (nephrectomy). The residual renal parenchyma on the native kidney contained non-sclerotic glomeruli. We retrospectively performed Jones staining which did not show irregularities of the glomerular basement membrane suggestive of membranous nephropathy. There was no available frozen sample

<figure><img src="image_3.png" /><figcaption>FIGURE 1 Protocol allograft kidney biopsies on month 3 and month 12. (A–C) Month 3 allograft kidney biopsy showing normal glomeruli on Masson Trichrome staining (A, × 200), negative C4d on peritubular capillaries and glomerular basement membrane (B, × 200) by immunohistochemistry, and negative PLA2R on glomerular basement membrane by immunohistochemistry (C, × 200). (D–F) Month 12 allograft kidney biopsy showing normal glomeruli on Masson Trichrome staining (D, × 200) but C4d immunohistochemistry revealed positive granular deposits along the glomerular basement membrane consistent with membranous nephropathy. Anti-PLA2R immunohistochemistry showed a positive staining of the extramembranous deposits. [Color figure can be viewed at wileyonlinelibrary.com]</figcaption></figure>
on the renal parenchyma. Hence, the diagnosis of de novo post-
transplant MN was firmly established. Screening for malignancy and
infections remained negative, excluding secondary causes of MN.
COVID-19 tests remained also negative (SARS-CoV-2 PCR was neg-
ative at MN diagnosis and 3 months after the diagnosis. Anti-Spike
IgG were negative 1 and 2 months after the diagnosis).

This is the first case of de novo posttransplant MN following
mRNA COVID-19 vaccine. Interestingly, cases of de novo or relaps-
ing MN after COVID-19 vaccine have recently been reported. ¹⁻³
Additionally, rare cases of MN (including one PLA2R+ case) have
been described after COVID-19 infection. ⁴

The temporality between COVID-19 vaccination and PLA2R+
MN in a patient without history of MN and in whom the etiolog-
ical workup has remained otherwise negative, supports a causal
link. However, we must acknowledge that a coincidental association
could not be ruled out.

Given the lack of proteinuria, no specific treatment was intro-
duced. The subclinical presentation of MN may be related to the mit-
igating effects of maintenance immunosuppressive therapy.

In conclusion, auto-immune reactivity and MN may occur after
mRNA COVID-19 vaccine. This report will raise awareness of ne-
phrologists for the need to closely monitor patients with primary
MN, following COVID-19 vaccination, including KTRs. If proteinuria
occurs after vaccination, a graft biopsy should be promptly per-
formed to firmly establish the diagnosis.

ACKNOWLEDGMENTS

We would like to thank Ms. Roberta Vellve for the English language
review.

DISCLOSURE

The authors of this manuscript have no conflicts of interest to dis-
close as described by the *American Journal of Transplantation*.

Nathalie Chavarot¹,²,³ ID

Michael Padden¹,²,³

Lucile Amrouche¹,²,³ ID

Stéphanie Malard⁴

Anne Scemla¹,²,³

Rebecca Sberro-Soussan¹,²,³

Juliette Léon¹,²,³ ID

Christophe Legendre¹,²,³

Jean Paul Duong³,⁵ ID

Julien Zuber¹,²,³ ID

Dany Anglicheau¹,²,³ ID

Marion Rabant³,⁵ ID

Pierre Isnard³,⁵

¹Department of Kidney and Metabolic diseases, Transplantation, and Clinical Immunology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

²Department of Immunology, Harvard Medical School, Boston, Massachusetts, USA

³Université de Paris, Paris, France

⁴Laboratoire Régional d'Histocompatibilité, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

⁵Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

Correspondence

Nathalie Chavarot, Service de Néphrologie et
Transplantation Rénale Adulte, Hôpital Necker-Enfants
Malades, 149, Rue de Sèvres, 75015 Paris, France.

Email: nathalie.chavarot@aphp.fr

ORCID

Nathalie Chavarot https://orcid.org/0000-0001-6361-1392

Lucile Amrouche https://orcid.org/0000-0003-1314-0312

Juliette Léon https://orcid.org/0000-0001-5314-8154

Jean Paul Duong https://orcid.org/0000-0002-3051-2141

Julien Zuber https://orcid.org/0000-0001-6741-9330

Dany Anglicheau https://orcid.org/0000-0001-5793-6174

Marion Rabant https://orcid.org/0000-0001-5696-6478

REFERENCES

1. Aydin MF, Yildiz A, Oruc A, et al. Relapse of primary membranous nephropathy after inactivated SARS-CoV-2 virus vaccination. *Kidney Int.* 2021;100:464-465. doi:10.1016/j.kint.2021.05.001

2. Da Y, Goh GH, Khatri P. A case of membranous nephropathy following Pfizer-BioNTech mRNA vaccination against COVID-19. *Kidney Int.* 2021;100(4):938-939. doi:10.1016/j.kint.2021.07.016

3. Gueguen L, Loheac C, Saidani N, Khatchatourian L. Membranous nephropathy following anti-COVID-19 mRNA vaccination. *Kidney Int.* 2021;S0085-2538(21):00757-00752. doi:10.1016/j.kint.2021.08.006

4. Nasr SH, Alexander MP, Cornell LD, et al. Kidney biopsy findings in patients with COVID-19, kidney injury, and proteinuria. *Am J Kidney Dis.* 2021;77(3):465-468. doi:10.1053/j.ajkd.2020.11.002

SUPPORTING INFORMATION

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