Outcomes of Covid-19 Vaccine-Associated Glomerular Diseases (CVAGD) – A Case Series from India

Introduction

The concerted effort to develop and expeditiously roll-out the Covid-19 vaccine has been hailed as one of the triumphs of 21^st century medicine. While the mRNA vaccines, Pfizer-BioNTech and Moderna were predominantly used in the West, the two vaccines widely available in India were Covaxin (BBV152), an inactivated virus vaccine, and Covishield (SII – ChAdOx1 nCoV-19), an adenoviral vector vaccine. Several case reports of glomerular diseases following Covid-19 vaccination have been reported in literature. However, follow-up data of these patients are scarce.

Materials and Methods

This was a prospective descriptive study conducted between May 2021 and May 2023. The study was approved by the Institutional Review Board and patient consent was obtained. All patients with new-onset proteinuria or proteinuric relapse, new-onset hematuria or decreased GFR within 30 days of Covid-19 vaccination were included. Clinical data, including preexisting kidney disease, vaccine type, time to onset of symptoms, and details of initial treatment were collected. Laboratory investigations, including serum creatinine, serum albumin, urine microscopy, and urine spot protein-creatinine ratio were done. Kidney biopsy was performed for all patients and tissue specimens were subjected to light microscopy and immunofluorescence. Details of management protocols and long-term renal outcomes were collected.

Categorical data were reported as numbers and percentage. Continuous data were reported as median with interquartile range (nonnormally distributed data) or mean with standard deviation (normally distributed data). As the sample size was small, descriptive statistics were used.

Results

Discussion

Autoimmunity associated with vaccination is a known phenomenon. Some of the autoimmune phenomena reported after Covid-19 vaccination are immune thrombocytopenic purpura, Guillain–Barré syndrome, rheumatoid arthritis, Graves’ disease, systemic lupus erythematosus, and several glomerular diseases. Molecular mimicry and cross-reactivity of antibodies can trigger autoimmunity. Secondarily, the vaccine adjuvant can activate inflammasomes and cause release of pro-inflammatory DAMPs such as IL-1α and HMGB 1 (high mobility group, box 1). This upregulation of immunological pathways in genetically predisposed individuals is the basis of immune-mediated diseases after Covid-19 vaccination.

While there have been several case reports of glomerular diseases occurring de novo or relapsing after Covid-19 vaccination, most of them are associated with mRNA vaccines. Furthermore, follow-up data on these patients remain scarce. This case series focuses on glomerular diseases triggered by Covaxin and Covishield vaccines and their long-term outcomes.

The majority of patients in our series developed symptoms after the first dose of vaccine, with a median time of 14 days after vaccination. Similar to results seen from other registries like IRocGN2, the most common glomerular lesions were MCD and IgAN while other lesions like C3 glomerulonephritis, FSGS, lupus nephritis, and ANCA-associated glomerulonephritis were less common.¹ The median age was 28 years (IQR 19.5) with a wide range from a 13-year-old boy with MCD to a 52-year-old lady with AAV. Another large series of CVAGD had an age range of 19–83 years, with most patients presenting after the second dose.²

The mRNA vaccines were used predominantly in the West, with the Pfizer and Moderna vaccines implicated in 54.1% and 19.4% patients, respectively, in the IRocGN2 registry.¹ In India, Covaxin and Covishield were extensively used. Covaxin (BBV152) is a whole-virion β-propiolactone-inactivated SARS-CoV-2 vaccine manufactured by Bharat Biotech. The adjuvant used was Algel-IMDG, an imidazoquinolinone molecule absorbed on alum. IMDG is a TLR7/8 agonist used to augment cell-mediated immune response, particularly Th1 response. In addition to a robust humoral response, BBV152 was shown to increase the CD4+ CD45RO+CD27+ T cell population, which implies activation of CD27 (co stimulatory molecule) and the antigen recall memory T-cell response. There is also generation of early IFN I, which helps in viral clearance and generation of pro-inflammatory cytokines.^3,4 Covishield (SII-ChAdOx1 nCoV-19) was manufactured in Serum Institute of India Pvt. Ltd. (SIIPL) after technology transfer from Oxford University/AstraZeneca. It is a recombinant, replication-deficient chimpanzee adenovirus vector that encodes SARS-CoV-2 spike glycoprotein. The E1 and E3 genes of the adenovirus were removed, which renders the virus incapable of replication. Inside the host cell, the virus breaks free from the endocytic vesicle and enters the nucleus where the host machinery is used to translate to S protein. This S protein is displayed on the cell surface by MHC I. Immunization with Covishield induces a robust T cell and antibody response. A predominant Th1 response has been demonstrated involving cytokines like IFN γ, IL 2, and TNFα/β.⁵

While there is insufficient data to claim causality, there is temporal association, biological plausibility, and good strength of association as relapses have been demonstrated after vaccine re-challenge.^6–12 In this series, only one patient presented after the second dose. He had minor symptoms after the first vaccine, which reappeared rapidly after the second dose.

Optimal management and long-term outcomes of CVAGD are not known; however, standard immunosuppressive regimens have been used. The overall response to treatment was good with 11 patients in complete remission and 4 in partial remission at the end of follow-up. It is unclear whether the immunologic mechanisms of injury in CVAGD are different from de novo glomerular diseases and a better understanding of the immune pathomechanisms in CVAGD would throw light on the potential for spontaneous recovery without immunosuppression.

Though this is one of the largest series from India with long-term outcome data on CVAGD, there are several limitations. The number of patients is small, likely due to the low incidence of the disease and possibility of missed cases. Furthermore, the strength of the association between vaccination and CVAGD could not be studied because of the absence of a control group. We also lack information on the safety of additional doses of vaccine as rechallenge was not attempted. Intriguing questions such as how to proceed with the vaccination schedule in patients who develop CVAGD remain unanswered, and it is not known whether changing the vaccine type would reduce risk.

This series highlights the wide array of glomerular lesions observed after Covid-19 vaccination, with MCD and IgAN being the most common. The overall long-term outcome of patients with CVAGD appears good. While causality cannot be proven, the temporal association between the presentation/relapse of glomerular diseases and Covid-19 vaccination, in the absence of other inciting factors, is persuasive. Long-term follow-up and collaborative studies are required for further understanding of the pathogenesis, immune mechanisms, and management of these diseases.