Exacerbation of Minimal Change Disease Following mRNA COVID-19 Vaccination

Background

The COVID-19 pandemic has prompted a global vaccination campaign, with numerous vaccines being developed and administered worldwide, which saved millions of lives globally. The Pfizer-BioNTech COVID-19 mRNA vaccine, BNT162b2, has shown remarkable safety and efficacy in preventing COVID-19, with a 95% effectiveness rate [1]. Renal injury following COVID-19 vaccination is a rare adverse event reported in some cases. Studies have shown that acute kidney injury (AKI) can occur after vaccination, particularly in elderly patients [2].

Minimal change disease (MCD) is a common cause of nephrotic syndrome, particularly in children. Its name – “minimal change” – refers to the lack of significant changes visible under light microscopy. The exact cause of MCD is often idiopathic (unknown), but it can also be secondary to certain factors such as infections (eg, tuberculosis and hepatitis C virus), neoplasms (eg, leukemia and lymphoma), allergies, drugs (eg, NSAIDs and antibiotics), and other glomerular diseases (eg, IgA nephropathy, SLE, diabetes mellitus, and HIV). MCD presents with proteinuria, resulting in edema and intravascular volume depletion. Notably, it shows a positive response to corticosteroid therapy. Diagnosis is made based on clinical presentation and laboratory tests, including urine analysis, urine collection for quantitating proteinuria, complete metabolic panel, complete blood count, and tests to rule out other secondary causes [3].

There are few reported cases of minimal change disease following COVID-19 vaccination, and most of the cases improved with steroid management [4]. Teragaki et al reported a case of relapse of minimal change disease (MCD) following the third dose mRNA COVID-19 vaccination in a 43-year-old man with a 29-year history of MCD [5].

Here, we report the case of a 33-year-old man with 22 years history of nephrotic syndrome due to minimal change disease exacerbated following a third dose of an mRNA SARS-CoV-2 vaccine for COVID-19.

Case Report

A 33-year-old man with a past medical history of nephrotic syndrome at age 11 presented to our clinic with bilateral lower-extremity swelling and frothy urine 10 days after receiving his third dose of the BNT162b2 mRNA COVID-19 vaccine. He also reported bilateral leg numbness and lower back pain. He had no recent history of trauma or falls, and no bowel or bladder incontinence was noted. He ambulated safely and had no recent changes in urine output. He reported no fevers or chills, nausea, vomiting, chest pain, shortness of breath, or abdominal pain, and had no prior history of similar symptoms. He had no recent travel history, no sick contacts, and no family history of autoimmune disease, coagulopathy, or neurologic disorders.

The patient quit smoking about 22 months prior to his symptoms, with his current tobacco use limited to chewing. He also reported current alcohol use and denied any illicit drug use. He was not taking any prescription or over-the-counter medications and had no history of nonsteroidal anti-inflammatory drug use.

Start vital sign with BP, heart rate, respiration rate, oxygen saturation, body temperature and BMI. His vital signs upon presentation were body temperature 36.7°C, blood pressure 167/107 mmHg, heart rate 95 bpm, respiration rate 18 bpm, and oxygen saturation 96% on room air, with a body mass index of 32.56 kg/m2. The physical examination was consistent with bilateral lower extremity edema.

The initial laboratory investigations revealed a serum creatinine level of 0.85 mg/dL, blood urea nitrogen of 14 mg/dL, albumin of 2.2 g/dL, and total protein of 5.2 g/dL. Urinalysis showed 3+ protein and 1+ blood, while the 24-h urine protein was 7.5 g, with a urine protein creatinine (UPC) of 9.3 g/g.

An immunologic workup, including PLA2R, hepatitis panel, HIV, IFE, Parvovirus, ANA, C3/C4, cryocrit, C-ANCA, P-ANCA, RPR, and nasopharyngeal COVID-19 polymerase chain reactions, provided no significant findings. An abdominal ultrasound confirmed mildly hyperechoic kidneys, suggestive of mild renal parenchymal disease, with no hydronephrosis, and a small non-obstructing right renal calculus.

Patient’s kidney biopsy (Figure 1) showed a cortex containing 33 glomeruli (3 globally sclerotic). The glomeruli were normal by light microscopy, without lesions of segmental sclerosis. There was minimal acute tubular epithelial cell injury and minimal interstitial fibrosis/tubular atrophy (<5%). There was no interstitial inflammation. Arteries and arterioles were un-remarkable. Immunofluorescence studies were significant for diffuse global weak punctate IgG, kappa and lambda podocyte cytoplasmic staining, and low-grade segmental granular mesangial staining for IgA (1+), IgM (1–2+), C3 (1+), and kappa and lambda light chains (both trace). Electron microscopy demonstrated complete podocyte foot process effacement associated with variable microvillous transformation of podocytes, as well as small electron-dense deposits in segmental mesangial regions. There were no tubuloreticular inclusions. No deposits displayed any substructure.

The findings in the biopsy were compatible with a diffuse podocytopathy with a minimal change disease phenotype and provided an anatomic etiology for the nephrotic syndrome. The low-grade mesangial deposits likely were latent IgA deposits or possibly a very low-grade IgA nephropathy, and provided an anatomic explanation for the hematuria. The presence of a delicate punctate IgG podocyte staining pattern raised the possibility of anti-nephrin antibodies as the mechanism of podocyte injury (commercial serologic testing for confirmation is currently unavailable).

The patient was started on 80 mg oral prednisone, which led to complete remission of disease in 4 weeks, with improvement of leg swelling and resolution of proteinuria. The dosage was tapered from 80 mg (47 days) to 60 mg (30 days), 40 mg (7 days), 30 mg (7 days), 20 mg (10 days), 10 mg (45 days), and 5 mg (60 days), and it was discontinued over the course of 28 weeks.

After 24 weeks of remission, the disease relapsed, with UPC increasing to 1.8 g/g; therefore, he was restarted on 60 mg of prednisone. Remission was achieved in 4 weeks with Alb/Cr <30 mg/g, UPC of 0.2 g/g, and normal kidney function with Cr=0.8 mg/dl in 4 weeks. Prednisone was tapered within 2 monthsafter achieving remission with resolution of proteinuria and complete remission to normal kidney function (Figure 2).

Discussion

This case report highlights the potential for COVID-19 vaccination to trigger relapses of minimal change disease (MCD), even after prolonged remission. The findings emphasize the importance of vigilant monitoring of proteinuria after vaccination in MCD patients and the need for further research into the mechanisms and management of vaccine-associated MCD.

An international multicenter study of 98 cases of de novo glomerulonephritis (GN) attributed to COVID-19 vaccines investigated data from 44 centers in 13 countries, showing that most of the patients had received mRNA vaccines, as in the present case, and identified minimal change disease (MCD) and IgA nephropathy (IgAN) as the most common diagnoses, with onset of GN suspected after the second vaccine dose in over half of the patients. MCD occurred more frequently after the first dose, while IgAN and other histologies were more commonly associated with the second dose. The most common kidney-related symptoms were edema, hypertension, foamy urine, and macroscopic hematuria, which occurred most frequently in IgAN, and few other diagnoses. Clinical presentations included nephrotic syndrome, sub-nephrotic-range proteinuria, microscopic hematuria, and isolated hematuria. The study found that 11% of cases of vaccine-induced GN were self-limiting, with complete or partial remission achieved in 60% of cases overall. Higher rates of remission were observed in MCD and IgAN cases (86% and 61%, respectively), while other subgroups had lower rates of remission [6].

In a retrospective population-level cohort study, the researchers used a centralized clinical and pathology registry to identify 1105 adult patients in British Columbia, Canada, with biopsy-proven glomerular disease that was stable on December 14, 2020. During 281 days of follow-up, 134 patients experienced a relapse. with exposure to a second or third vaccine dose associated with a 2-fold higher risk of relapse, but a first vaccine dose was not associated with relapse risk (HR=0.67) [7].

A recent study investigated whether nephrin autoantibodies were present in patients with minimal change disease and explored the potential autoimmune etiology of the disease. The researchers evaluated sera from 2 independent patient cohorts for circulating nephrin autoantibodies, using various methods, and identified their presence during active disease, which was significantly reduced or absent during treatment response in a subset of patients with minimal change disease. They also correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies and identified a patient with steroid-dependent childhood minimal change disease who developed a massive post-transplant recurrence of proteinuria associated with high pretransplant circulating nephrin autoantibodies. The discovery of nephrin autoantibodies in patients with minimal change disease agrees with published animal studies and provides further support for an autoimmune etiology [8].

The pathogenesis of vaccine-associated minimal change disease has been hypothesized, in which vaccine-induced immune response may trigger the production of cytokines, which leads to podocyte damage [9]. It has also been suggested that the vaccine may act as a trigger for a pre-existing autoimmune process [10]. There was very low-grade segmental mesangial IgA deposition. This may represent a low-grade IgAN, which has also been seen following COVID and Vaccines, or latent IgAN deposits, which are not uncommonly encountered in kidney biopsies, without clinical significance. This likely was not a significant factor in the nephrotic presentation. Our case report’s strength lies in its potential to contribute to the evolving understanding of renal disorders occurring after COVID-19 vaccination. By considering antibody-based evidence, evaluating mesangial IgA deposition, and juxtaposing MCD and IgAN within the broader context of vaccine-related nephropathies, this report adds to the discourse on the intricacies of renal responses to vaccination.

Conclusions

This report presents a case of longstanding minimal change disease which shows exacerbation following a third dose of an mRNA vaccine for SARS-CoV-2. Although this may be a rare association, this case supports that patients with glomerulonephritis needed to be monitored after vaccination for COVID-19. Further studies are needed to understand the relationship between COVID-19 vaccination and nephropathies, as well as optimal management strategies for these rare but potentially serious adverse events in relapsing cases.