COVID-19 Vaccination and De Novo Glomerular Disease: Causation or Coincidence?

Given the increased risk of hospitalization and mortality from SARS-CoV-2 infection and COVID-19, vaccination against SARS-CoV-2 is strongly recommended for patients with preexisting chronic kidney disease and glomerular disease (1, 2). However, a growing number of case reports have highlighted a possible link between de novo glomerular disease and COVID-19 vaccines, particularly mRNA vaccines (Pfizer-BioNTech and Moderna) (3–6). Whereas a potential association between vaccines and glomerular disease is not a novel phenomenon, with influenza vaccine-associated glomerulopathies being the most commonly cited (7), the overall risk appears minimal and drastically lower than the adverse health consequences of infection with the microbial targets of recommended vaccines.

In a recent issue of Kidney360, Waldman et al. (8) reported the results of the International Registry of COVID-19 Vaccination and Glomerulonephritis (IRocGN2), a National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health-launched registry to study COVID-19 vaccine-associated glomerular diseases (CVAGDs). Inclusion criteria required de novo biopsy-proven glomerular diseases and vaccine dose given within 3 months of biopsy. A total of 98 cases were entered in IRocGN2 over 11 months, encompassing 44 centers internationally. The majority of patients were from the United States, were White, and had received mRNA vaccines (Figure 1). Immunoglobulin A nephropathy (IgAN) and minimal change disease (MCD) were most commonly reported, followed by Pauci-immune crescentic glomerulonephritis and membranous nephropathy. Although most pathologies occurred after the second vaccine dose, MCD presented more frequently after the first dose.

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Timeline and summary from the IRocGN2

Citation: Kidney News 15, 3

FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; HTN, hypertension; RAASi, renin-angiotensin-aldosterone inhibition.

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The age distribution of CVAGDs reflected those of glomerular diseases in the general population. Patients who were Black/African Americans represented only a small percentage of cases but disproportionately had collapsing glomerulopathy; high-risk APOL1 genotypes were found in two-thirds of patients. In 75% of cases, kidney-related symptoms were seen within 2 weeks of vaccine administration. At biopsy, the median proteinuria was 4 g/g (interquartile range [IQR], 2–9), creatinine was 1.7 mg/dL (IQR, 1.0–3.7), and the estimated glomerular filtration rate was 42 mL/min/1.73 m² (IQR, 15–81).

Renin-angiotensin inhibition was implemented in 30% of cases, and 60% of patients received immunosuppression. Over a median follow-up of 89 days (IQR, 27–177), complete or partial remission occurred in 60% of patients, with the highest remission rates seen in MCD and IgAN. Spontaneous recovery occurred in 11% of patients. Dialysis was required for 9% of patients, mainly due to anti-glomerular basement membrane disease or Pauci-immune crescentic glomerulonephritis.

The authors detailed the difficulties of assigning causality to vaccines, given the possible subtlety of kidney-related signs and symptoms, the lack of specificity for one particular COVID-19 vaccine (or COVID-19 vaccines in general), and the need for elucidation of potential mechanisms underlying CVAGDs. It must be noted that the cases identified in this registry could also represent background disease prevalence across the population, given that 60%–70% of all individuals in the world received the vaccination over a discreet time period. Conversely, the recurrence of glomerular disease following vaccine re-challenge in six patients strengthened the possibility of causality, although follow-up data were limited.

This study represents the largest published series to date of de novo glomerular disease cases temporally associated with COVID-19 vaccination. In the future, data from diverse patient populations with expanded serological testing over an extended follow-up period will help define the overall risk of CVAGDs, identify potential high-risk subgroups, and explore vaccine re-challenge. Although it is important to enhance our understanding of CVAGDs, the overall risk appears very low and should not alter current recommendations for COVID-19 vaccination in patients with kidney diseases, even those with known glomerular diseases. Moreover, the majority of cases identified in this registry as potentially being associated with vaccination achieved complete or partial remission.

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