New Onset Glomerular Disease Post-COVID-19 Vaccination: Is There a Link?

The coronavirus disease 2019 (COVID-19) is an ongoing pandemic that has been associated with an estimated 15 million deaths worldwide and over one million deaths in the United States alone.1 Although the mortality rate and risk of severe disease have significantly reduced after the development and administration of COVID-19 vaccines, vaccine acceptance has not been universal.2 This is in part due to concerns regarding potential side effects associated with the vaccine. One such side effect is the development of de novo GN or relapse of an existing one after vaccination with growing number of studies, mostly case series and retrospective analysis, reporting on such side effects since vaccine roll out.3 It has been hypothesized that the COVID-19 vaccine may lead to the development of GN by inducing a robust immune response and possibly an aberrant antibody formation (such as galactose deficient IgA1 antibodies),4 dysregulated T-cell activation (that may be associated with podocyte injury),5,6 molecular mimicry (in which antibody response to severe acute respiratory syndrome coronavirus-2 spike protein could cross-react against host tissue),7 and exposure of hidden self-antigens during a vaccine-mediated immune response.8 More recently, a study from the Swiss Pathology Database showed that the observed incidence of GN during the 8 months after initiation of COVID-19 vaccination was the same as the expected incidence of GN from prior years.9 This raises the question as whether there is truly an increase in incidence of GN after the introduction of vaccines or whether this noted association is just a coincidence and has to do with the fact that a large portion of the population was vaccinated in a short span of time during which some patients were going to develop GN with or without the vaccine. In this issue of Kidney360, Waldman and colleagues studied the development of de novo GN after vaccination against severe acute respiratory syndrome coronavirus-2 and they present the results from the International Registry of COVID-19 Vaccination and Glomerulonephritis.10 In this study, practicing providers enrolled patients in the registry (both prospectively and retrospectively) if the patient was diagnosed with new-onset biopsy-proven GN within three months of receiving at least one dose of COVID-19 vaccine. The data were collected through International Registry of COVID-19 Vaccination and Glomerulonephritis registry in which providers were able to voluntarily report and modify prevaccination (baseline), postvaccination (at the time of kidney biopsy), and follow-up data that included demographics, clinical symptoms, laboratory values, biopsy results, vaccine information, and outcomes. A total of 98 de novo GN cases were reported in the span of 10 months during which the study was conducted. Most (73%) received the mRNA vaccine (54% BNT162b2 and 19% mRNA-1273) followed by vector vaccines (12%). The most common kidney-related signs and symptoms included edema (54%), hypertension (41%), foamy urine (34%), and macroscopic hematuria (34%). In most patients (75%), symptoms developed within 2 weeks of vaccination. The most common histopathological findings on the biopsy were minimal change disease (MCD) (29%), IgA nephropathy (IgAN) (27%), pauci-immune GN (17%), and membranous nephropathy (10%). Other reported histopathological findings included antiglomerular basement membranedisease and collapsing glomerulopathy. Up to 60% of the patients received immunosuppression with corticosteroids alone or in combination with anti-CD20 therapy, cyclophosphamide, mycophenolate, or calcineurin inhibitors. Complete or partial remission with or without immunosuppression was noted in 60% of the patients. MCD and IgAN were noted to have a more favorable prognosis, and patients were more likely to achieve remission compared with other diagnosis with 86% and 61% response rates, respectively. Overall, 16% had persistent proteinuria, 14% did not have any response to treatment, 9% required dialysis, and 5% died (one of whom had required dialysis). This is the first study to evaluate the development of de novo GN after vaccination from a large number of centers (44) in at least 13 countries which allows for a better representation of the patients from across the globe. Another strength of the study is that all diagnoses (except for one patient with positive anti-phospholipase 2 receptor) were biopsy proven. This study further confirms what has been seen in previous studies with most common lesion postvaccination being MCD (commonly seen in association with Pfizer vaccine and symptoms presenting after the first dose) followed by IgAN (more commonly seen in association with Moderna vaccine and symptoms developing after the second dose of vaccine).3,11 An optimistic assessment of the results would be that most patients (60%) with the common presentations of MCD and IgAN had favorable outcomes with improvement in their proteinuria and stability of their eGFR overtime. However, another way of assessing the data would be that 40% of the patients did not have a favorable outcome, and overall, there was a 20 ml/min per 1.73 m2 decline in eGFR overtime (from baseline of 90 to 70 ml/min per 1.73 m2). This is not an insignificant drop especially when considering a younger population (mean age of 48 years). Those with nephritic presentations (e.g., pauci-immune GN and antiglomerular basement membrane) did poorly with significant loss of eGFR overtime with 9% requiring dialysis. It is important to note that the duration of follow-up in this study was very short (3 months), and longer-term data are needed to determine the long-term prognosis of such patients. Despite all the important information that this study was able to capture, it was unable to answer several important key questions: (1) What was the occurrence of de novo GN during this 10-month period in patients who did not get vaccinated? This is a hard question to answer but an important one. If we are to get clarity on whether there is a true association between the vaccines and development of GN, it is important to show that indeed there is an increase in the number of cases of de novo GN postvaccination compared with nonvaccinated individuals. This point was elegantly evaluated in a recent study by Canney et al. in which they were able to show that the rate of GN relapses post–COVID-19 vaccination had a two-fold increase compared with nonvaccinated individuals after second and third dose of the vaccine (albeit the absolute risk was small).12 (2) Are these de novo GN diagnoses truly new diagnoses or did the patient already have the disease that went unrecognized and only came to medical attention because the patient was vaccinated? In this study, 16% of the patients had a diagnosis of CKD before vaccination, and although the CKD diagnosis was not attributed to an underlying GN, it does raise that possibility. In one of the case series of GN post–COVID-19 vaccination, we were able to show that in one patient who was diagnosed with “new” IgAN post–COVID-19 vaccination, the IgA deposits were already present several years before receiving the COVID-19 vaccine (after reviewing sample from prior nephrectomy) and the disease was subclinical.11 (3) What was the incidence of developing de novo GN after vaccination? It would be important to know during this 10-month period of the study in which 98 patients were diagnosed with GN (assuming all patients were captured which is a big assumption and likely incorrect—a point further addressed below), how many patients were vaccinated and did not develop GN? This would allow patients and care providers to be able to better assess the risks of vaccination. This point has been extensively studied when evaluating the risk of other side effects associated with COVID-19 vaccination, namely myocarditis. The risk is highest in male younger than 30 years, and this subgroup of 1,000,000 doses of vaccine administered, 39–47 individuals, can develop myocarditis.13 However, in this same subgroup, the 1,000,000 doses of vaccine can prevent 560 hospitalization, 138 intensive care unit admissions, and 6 deaths.13 Based on these data, one can then make an informed decision about the risk and benefit ratio of vaccination. In the context of assessing risks and benefits, it is also important to remember that COVID-19 infection itself is associated with increased risk of developing GN and decline in kidney function and this risk should be considered when discussing vaccinations with individuals.14–17 When estimating the incidence, it is also important to point out that not all patients were captured in this study either. This was based on self-reporting by the providers, and some cases may not have been reported, and similarly, not all patients may seek medical care or see a provider within the 3-month period postvaccination. Although certain symptoms such as macroscopic hematuria or foamy urine may make patients seek care, other symptoms of kidney disease may go unrecognized. (4) Which patients were more likely to develop this potential side effect? In this study, the age ranged from 15 to 79 years representing a wide spectrum and cases were distributed equally between both sexes and from different ethnic backgrounds. Data in this regard are lacking, and more information is needed. (5) In a patient who has developed a new GN postvaccination, are additional doses of vaccine or boosters safe? In this study, there are only data available on six patients who were rechallenged (3 with MCD and 3 with IgAN), and all relapsed, although unclear how many were rechallenged and did not have a relapse. This is yet another study evaluating the potential link between COVID-19 vaccination and risk of developing de novo GN. Physicians should be aware of this potential side effects postvaccination. Although the cases may not all be truly new diagnosis, the development of symptoms could be a sign that a subclinical case has become evident. A prompt and comprehensive evaluation of the patient is needed to rule out an underling GN should the patient develop any signs or symptoms. More data are needed to establish a link between COVID-19 vaccination and development of GN by evaluating the risk in those who have not been vaccinated, establishing the rate of such complication, identifying those who are at risk, and understanding risk of relapse when such patients are rechallenged. This study shows that collaboration among centers and countries is the key to solving and answering these essential questions.