Introduction

Messenger RNA (mRNA) vaccines against the coronavirus disease 2019 (COVID-19) have rapidly emerged. These vaccines are a critical tool for controlling the COVID-19 pandemic [1, 2]. However, adverse events following vaccination remain unclear. Several reports have described cases of new-onset or relapse of minimal change disease (MCD) after COVID-19 vaccination [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Herein, we report a case of MCD relapse following the third dose of the Pfizer-BioNTech COVID-19 vaccine in a patient with MCD in long-term remission. Previously published cases of MCD following COVID-19 vaccination are summarized briefly.

Case report

A 43-year-old man with a history of nephrotic syndrome was referred to nephrology service due to frothy urine and lower limb edema, which occurred 4 days after receiving the third dose of the Pfizer-BioNTech COVID-19 vaccine. He developed nephrotic syndrome at the age of 3 years and underwent a kidney biopsy at the age of 6 years, which provided a diagnosis of MCD. He has been in drug-free remission since the age of 14 years. He had received the first and second doses of the Pfizer-BioNTech COVID-19 vaccine 9 and 8 months before his admission, respectively, with no adverse events. There were neither preceding infections nor drug use, which could trigger the nephrotic syndrome.

On admission, physical examination revealed marked generalized edema and weight gain of 13 kg. His blood pressure was 151/98 mmHg, pulse rate was 69 beats/min, and respiratory rate was 18/min with an oxygen saturation of 98% on room air. Urinalysis diagnosed 3 + proteins without red cells. The 24-h urinary protein excretion was 5.12 g/day; selectivity index for proteinuria was 0.11. Laboratory tests revealed a serum creatinine level of 1.0 mg/dL, estimated glomerular filtration rate of 66 mL/min/1.73m2, albumin level of 1.7 g/dL, and low-density lipoprotein cholesterol level of 226 mg/dL. Complete blood count and coagulation test results were normal. Serological workup revealed no signs of an underlying systemic disease or malignancy. Chest X-ray film showed bilateral pleural effusions. As measured by the chemiluminescent immunoassay (Abbott Laboratories), the level of serum IgG antibodies to the SARS-CoV-2 spike protein was elevated to 6639 AU/mL on the 30th day after vaccination.

A kidney biopsy was performed to evaluate nephrotic syndrome. Light microscopy showed global sclerosis in one glomerulus and no abnormalities in the remaining 52 glomeruli (Fig. 1a, b). Tubular atrophy and interstitial fibrosis were absent, and mild hyalinosis of arterioles was observed (Fig. 1a, b). The immunofluorescence studies including IgG, IgA, IgM, and C3 were all negative. Electron microscopy revealed diffuse foot process effacement with no electron-dense deposits (Fig. 1c, d). Based on these findings, MCD relapse was diagnosed. Intravenous methylprednisolone was initiated at 1000 mg for 3 days followed by prednisolone at 1 mg/kg daily. He responded well to steroid therapy and achieved complete remission of the nephrotic syndrome within 3 weeks. At 7 months after the initiation of treatment, he remained in complete remission with 7.5 mg of prednisolone.

Fig. 1
figure 1

Kidney biopsy findings. Light microscopy of representative glomerulus stained by a periodic acid–methenamine silver (original magnification, × 100) and b periodic acid–Schiff (original magnification, × 400), demonstrating minor glomerular abnormality. Hyalinosis of an arteriole is observed (arrow). c, d Electron microscopy reveals diffuse podocyte effacement without electron–dense deposits (original magnification, × 1500 and × 6000, respectively)

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Discussion

We report the case of MCD relapse following the third dose of the Pfizer-BioNTech COVID-19 vaccine. In the present case, MCD had been in remission for 29 years but relapsed a few days after the third vaccination. There were no triggers of an MCD relapse; therefore, the vaccination seemed to have caused the relapse. In July 2021, Lebedev et al. first reported a case of new-onset MCD after receiving the first dose of the mRNA COVID-19 vaccine [3]. Since then, reports of new-onset or MCD relapse following COVID-19 vaccination have been increasing [5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. The timing of MCD onset or relapse was reported at a median of 7 days after the first dose of the COVID-19 vaccine [4]; however, details of clinical characteristics of COVID-19 vaccine-associated MCD are unknown. We summarized the cases of new-onset and relapsed MCD following COVID-19 vaccination to determinate the clinical characteristics.

We identified 34 cases of relapses MCD and 30 cases of new-onset MCD following COVID-19 vaccination. The clinical characteristics of cases of MCD relapse and the present case are summarized in Table 1 [5,6,7,8,9,10,11,12,13,14,15]. 28 of 34 cases relapsed after receiving mRNA-based vaccines: 24 cases after receiving the Pfizer-BioNTech vaccine and four cases after receiving the Moderna vaccine. 23 cases (68%) of MCD relapse occurred after the first dose of the COVID-19 vaccine, nine cases (26%) occurred after the second dose, and two cases (6%) occurred after the third dose. In 14 cases (41%), relapse occurred within 10 days after the COVID-19 vaccination. Meanwhile, 30 cases of new-onset MCD following COVID-19 vaccination have been reported (Table 2); 23 cases (77%) developed MCD after the first dose, and 22 cases (73%) were diagnosed within 10 days after vaccination [3, 5, 6, 14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]. Given these findings, new-onset MCD tended to appear earlier after vaccination and to occur slightly more often after the first dose of vaccine than MCD relapse. Of the 34 MCD relapse cases, 26 were in drug-free remission, while 5, including the present case, occurred > 15 years after complete remission; almost all cases promptly achieved remission following steroid therapy.

Table 1 Case reports of minimal change disease (MCD) relapse following COVID-19 vaccination
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Table 2 Case reports of new-onset minimal change disease following COVID-19 vaccination
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Considering that more than 13 billion doses of vaccines against COVID-19 have been administered worldwide [37], the development of MCD might occur coincidentally following COVID-19 vaccination. However, there have been few reports of MCD after receiving other vaccines: only three cases following influenza vaccination and one case following hepatitis B vaccination [38,39,40,41], although these vaccines have been extensively used. Moreover, MCD which had been in long-term remission (> 15 years) relapsed shortly after vaccination without other identifiable trigger not only in our case but also in other four cases [6, 9, 13]. These findings indicate that there appears to be some link between MCD development and COVID-19 vaccination. Further research is needed to investigate their association.

The precise pathogenesis of MCD is not fully understood; however, many studies suggest that MCD results from dysregulation of T cells, which leads to cytokine production and subsequent podocyte injury [42,43,44]. The mRNA vaccine against COVID-19 induces T cell activation and cytokine release, including interferon-γ, in healthy individuals [45]. Therefore, some reports have speculated that mRNA vaccine-induced T cell activation and cytokine release may play a role in the development of MCD [3, 4, 46]. In the present case, MCD relapsed after the third dose of the mRNA vaccine despite the absence of adverse events after the previous two vaccinations. A recent publication showed that the secondary or booster vaccinations notably enhanced cytokine secretion compared to the first vaccination [47,48,49]. This exaggerated immune response through additional vaccinations might finally trigger a relapse of MCD in susceptible patients. The optimal treatment strategy of COVID-19 vaccine-associated MCD has not been established. In our literature review, almost all cases were treated with steroid therapy and achieved disease remission; however, interestingly, one case of new-onset MCD achieved a spontaneous remission by 6 weeks without any medical treatment. Further cases and studies are required to investigate the pathogenesis and treatment of MCD following COVID-19 vaccination.

In summary, we present a case of MCD relapse following the third dose of mRNA COVID-19 vaccination in a patient with MCD who had been in long-term remission. Our case and literature review of COVID-19 vaccine-associated MCD indicate that MCD relapse tends to occur later after vaccination and slightly more often following the second and subsequent vaccinations compared to de novo MCD. Clinicians need to be aware of this association and closely monitor proteinuria in a patient with MCD who had received COVID-19 vaccines even if there have been no adverse events during previous vaccinations.