Atypical Anti-Glomerular Basement Membrane Nephritis After the First Dose of the Severe Acute Respiratory Syndrome Coronavirus 2 mRNA Vaccine

ABSTRACT

Atypical anti-glomerular basement membrane (GBM) nephritis is a slowly progressive characterized by linear deposition of immunoglobulin (Ig) G in the GBM without circulating anti-GBM antibodies or lung involvement. There is no established therapy for this disease, and efficacy of the immunosuppressive treatment is questionable. A few cases of atypical anti-GBM nephritis have been reported after administration of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Classic anti-GBM disease has also been reported after the administration of the second dose of the SARS-CoV-2 vaccine. Herein, we present the case of a SARS-CoV-2 vaccine-induced atypical anti-GBM nephritis that developed after the first dose and was unresponsive to immunosuppressive therapy. A 57-year-old Japanese woman developed edema 11 days after the first dose of the SARS-CoV-2 mRNA vaccine. She developed nephrotic-range proteinuria and microscopic hematuria. Renal biopsy revealed endocapillary proliferative glomerulonephritis with linear IgG deposition. However, electron-dense deposits were not detected on electron microscopy. The patient tested negative for circulating anti-GBM antibodies and was diagnosed with atypical anti-GBM nephritis. Although steroids and mizoribine were administered, the patient’s renal function deteriorated. In conclusion, atypical anti-GBM nephritis may have earlier onset than the classic anti-GBM disease. Given its uncertainty of effectiveness, immunosuppressive agents should be carefully used for SARS-CoV-2 mRNA vaccine-induced atypical anti-GBM nephritis.

Anti-glomerular basement membrane (GBM) disease is a rare autoimmune disease caused by the development of antibodies against the non-collagenous domain of the type IV collagen alpha3 chain in the basement membranes of glomerular and alveolar capillaries. Anti-GBM disease typically manifests as rapidly progressive glomerulonephritis with a poor prognosis. If alveolar hemorrhage is present, the entity is known as Goodpasture syndrome.

Atypical anti-GBM nephritis is a slowly progressive variant, with linear immunoglobulin (Ig) G deposition in the GBM and no pulmonary involvement or circulating anti-GBM antibodies.^{1, 2} However, the difference in pathogenesis between the classic anti-GBM disease and atypical anti-GBM nephritis remains unknown. Moreover, there is no evidence-based treatment protocol for atypical anti-GBM nephritis currently, and the therapeutic efficacy of the immunosuppressive drugs used is questionable. Autoimmunity against GBM is the fundamental pathogenic mechanism underlying the development of classic anti-GBM disease, which is triggered by infections or exposure to environmental factors.³ Recently, several cases of classic anti-GBM disease have been reported after the administration of the second dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine.^4,5,6,7 However, the incidence of SARS-CoV-2 vaccine-induced atypical anti-GBM nephritis remains scarce. Herein, we report a case of atypical anti-GBM nephritis that developed following the administration of the first dose of SARS-CoV-2 mRNA vaccine. Furthermore, we have summarized the findings of previous reports on vaccine-induced classic anti-GBM disease and atypical anti-GBM nephritis.

PATIENT REPORT

A 57-year-old Japanese woman with a history of hypertension developed facial puffiness and lower limb edema 11 days after receiving the first dose of SARS-CoV-2 mRNA vaccine. At the primary healthcare center, a urinalysis revealed proteinuria and hematuria. The patient was referred to another hospital, but she could not undergo a complete evaluation. The patient received her second vaccine dose 21 days after the first dose. Two days later the patient was referred to our hospital for further evaluation and treatment of edema.

At the presentation, the patient presented with mild pedal edema, weighed 50.3 kg, and had a body temperature of 36.8°C. She did not have a history of smoking. Ultrasonography revealed the absence of any morphological abnormalities of the kidneys. Chest radiography showed no abnormal findings in the lung or pleural effusion. Her laboratory data at presentation were as follows: serum creatinine level, 0.85 mg/dL; serum albumin level, 3.1 g/dL; C-reactive protein level, 0.05 mg/dL; urine protein-to-creatinine ratio, 7.22 g/gCr; and red blood cells in urinary sediment, 50–99/high-power fields (Table 1). The hemoglobin A1c level was 5.5% (Table 1), and the 75 g oral glucose tolerance test result was normal. Immunological examination revealed negative test results for anti-GBM antibodies (2.9 U/mL via fluorescence enzyme immunoassay; normal range < 7.0 U/mL) and antineutrophil cytoplasmic antibodies. Furthermore, there was no increase in the Ig and myeloma protein levels (Table 1). Physical and laboratory examinations did not reveal any apparent signs of infection.

Table 1. Laboratory data at the time of presentation.

Urinalysis			Biochemistry
Specific gravity	1.006		Sodium	144	mmol/L
pH	6.5		Potassium	3.5	mmol/L
Protein	2+		Chloride	108	mmol/L
Sugar	–		Calcium	8.4	mg/dL
Occult blood	3+		Glucose	94	mg/dL
Red blood cell	50–99		HbA1c	5.5	%
White blood cell	1–4		Estimated GFR	53.67	mL/min/1.73m2
Protein-to-creatinine ratio	7.22	g/gCr	Immunological test
β2 microglobulin	444	μg/L	C-reactive protein	0.05	mg/dL
NAG	4.7	U/L	IgG	854	mg/dL
Complete blood count			IgA	207	mg/dL
White blood cell	2450	/μL	IgM	3	mg/dL
Red blood cell	321 × 104	/μL	C3	93	mg/dL
Hemoglobin	9.7	g/dL	C4	28	mg/dL
Hematocrit	28.8	%	CH50	53.3	U/mL
Platelet	17.5 × 104	/μL	κ FLC	18.3	mg/L
Biochemistry			λ FLC	21.9	mg/L
Total protein	5.4	g/dL	κ/λ FLC ratio	0.84
Albumin	3.1	g/dL	Myeloma protein	Negative
AST	24	U/L	HBs antigen	< 0.05	U/mL
ALT	20	U/L	Anti-HCV antibody	0.04	S/CO
ALP	40	U/L	MPO-ANCA	< 0.5	U/mL
γ-GT	12	U/L	PR3-ANCA	< 0.5	U/mL
LD	307	U/L	Anti-GBM antibody	2.9	U/mL
Total bilirubin	0.4	mg/dL	ANA	< 40
Creatinine	0.85	mg/dL
Urea nitrogen	18.2	mg/dL

ANA, antinuclear antibody; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; C3, complement component 3; C4, complement component 4; CH50, 50% hemolytic complement; FLC, free light chain; γ-GT, γ-glutamyltransferase; GBM, glomerular basement membrane; GFR, glomerular filtration rate; HbA1c, hemoglobin A1c; HBs, hepatitis B surface; HCV, hepatitis C virus; Ig, immunoglobulin; LD, lactate dehydrogenase; MPO-ANCA, myeloperoxidase-antineutrophil cytoplasmic antibody; NAG, N-acetyl-β-d-glucosaminidase; PR3-ANCA, proteinase 3-antineutrophil cytoplasmic antibody.

A kidney biopsy was performed 32 days after the first vaccination dose. Light microscopy revealed 23 glomeruli, of which two had global sclerosis, and one had a fibrous crescent. Endocapillary hypercellularity was prominent. Some glomeruli showed mesangial proliferation and mild lobulation (Figs. 1a–d). Doubling of the GBM was noted, but spike formation of the GBM was not noted. However, features suggestive of diabetic nephropathy, such as diffuse glomerulosclerosis and nodular glomerular lesions, were not visualized. Mild interstitial fibrosis and moderate sclerosis of the small arteries were observed. Immunofluorescence revealed linear IgG and mild granular IgA and complement component 3 deposits on the capillary wall (Figs. 1e–h). Further IgG subclass analysis could not be performed at our hospital. Immunohistochemistry revealed mild granular deposition of kappa and lambda chains in the GBM (Figs. 1i and j). Electron microscopy did not reveal any electron-dense deposits in the glomerulus; however, extensive effacement of the podocyte foot processes was detected (Figs. 1k and l). These findings led to a diagnosis of atypical anti-GBM nephritis.

Fig. 1.

 Histopathological findings of the kidney biopsy. Light microscopy showing endocapillary hypercellularity (a and b) and focal lobulation (c and d). Immunofluorescence showing bright linear immunoglobulin G (e) and mild granular immunoglobulin A (f) and complement component 3 (h) deposition on the capillary wall; no accumulation of immunoglobulin M (g). Immunohistochemistry revealed granular deposits of kappa (i) and lambda (j) light chains on the capillary wall. Electron microscopy showed no electron-dense deposits in the glomerulus and extensive loss of podocyte foot processes (k and l). a and c: Periodic acid-Schiff stain. b and d: Periodic acid-methenamine silver stain. a–d, i and j: Bar = 50 μm. k: Bar = 10 μm. l: Bar = 5 μm.

Fifty-two days after the first vaccination dose, pulse therapy of 500 mg methylprednisolone was administered for three days. Thereafter, 50 mg of oral prednisolone was initiated. Owing to the lack of therapeutic efficacy three weeks after treatment, she was concomitantly administered mizoribine. However, the proteinuria did not decrease and renal function worsened. On tapering prednisolone to 20 mg, the patient developed varicella-zoster virus encephalitis, requiring discontinuation of mizoribine and administration of acyclovir for three weeks. Subsequently, the proteinuria reduced, and the serum creatinine levels decreased slowly. Anti-GBM antibody titers were estimated repeatedly; they were not detected. Fourteen months after the first vaccination dose, the serum creatinine levels stabilized at approximately 1.8 mg/dL; the urine protein-to-creatinine ratio was approximately 0.5–1.5 g/gCr (Fig. 2).

Fig. 2.

 Clinical course. Eleven days after the first dose of the SARS-CoV-2 vaccine, the patient developed mild edema, microhematuria, and nephrotic-range proteinuria. She received steroid pulse therapy followed by high-dose oral corticosteroids and mizoribine. However, her kidney function deteriorated. She contracted varicella-zoster virus encephalitis, and thus, mizoribine was discontinued. After the treatment for herpes zoster, the proteinuria decreased, and the kidney function stopped deteriorating. m-PSL, methylprednisolone; PSL, prednisolone; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

DISCUSSION

Herein, we described a case of atypical anti-GBM nephritis that developed after the first dose of the SARS-CoV-2 vaccine. This case highlights two points: (i) atypical anti-GBM nephritis may have an earlier onset than classic anti-GBM disease; and (ii) immunosuppressive therapy may be ineffective in vaccination-induced atypical anti-GBM nephritis.

The present case developed atypical anti-GBM nephritis after the SARS-CoV-2 vaccination. However, the causal association between the vaccine and anti-GBM disease, including atypical anti-GBM nephritis, remains unclear. Atypical anti-GBM nephritis is considered to share a similar pathology to classic anti-GBM disease;^{1, 2, 8} environmental factors such as infectious diseases may seemingly induce atypical anti-GBM nephritis. No other trigger could be identified in this patient apart from the SARS-CoV-2 vaccine. A regional increase in anti-GBM disease incidence was reported during the coronavirus disease 2019 (COVID-19) pandemic in one study.⁹ Although five of the eight patients in the study tested negative for SARS-CoV-2 infection by polymerase chain reaction, four had IgM antibodies against SARS-CoV-2, suggesting that a recent infection may be involved in the development of anti-GBM disease. No evidence of an increased incidence of atypical anti-GBM nephritis during the COVID-19 pandemic has been reported, likely because the concept of the disease is new and its occurrence is extremely rare.

Atypical anti-GBM nephritis may have an earlier onset than classic anti-GBM disease after vaccination for SARS-CoV-2. Recently, SARS-CoV-2 vaccine administration has been suggested as a trigger for the classic anti-GBM disease. Four such cases have been reported after administration of the second dose of the mRNA vaccine (Table 2).^4,5,6,7 The first case, which was reported in 2021, involved a 60-year-old woman with only kidney involvement; the lungs were spared.⁴ To date, there has been only one other case of mRNA vaccine-induced atypical anti-GBM nephritis after the first dose.¹⁰ Recently, two cases of classic anti-GBM disease were reported after administration of an adenoviral vector-based vaccine: one occurred eight weeks after the first dose, and the other three weeks after the second dose.¹¹ The reported onset time was even later than that in the cases after administration of the mRNA vaccine. Whether the classic or atypical variant, anti-GBM disease following vaccination against SARS-CoV-2 was a new onset.^{4,5,6,7, 10, 11} The lack of circulating antibodies in atypical anti-GBM nephritis suggests that there may be undetectable autoantibodies or antibodies specific to GBM antigens.^{1, 2, 8} Although the difference in pathogenesis between atypical anti-GBM nephritis and classic anti-GBM disease remains unclear, the difference in onset time may reflect this difference in pathogenesis.

Table 2.  Overview of our case and previously reported cases of anti-GBM diseases.

REFs	Age/sex	Vaccine	Disease-inducing dose	Time from vaccine to onset	Lung lesion	Anti-GBM antibody (U/mL)	Therapy	FU time (mo)	Laboratories at presentation/last FU
									Cr	Urine protein
Classic anti-GBM disease
4	60/F	BNT162b	2nd	1 day	Yes	10.0 RR < 7.0	S, PE, POCY	NA	541/NA (μmol/L)	7.6/NA (g/gCr)
5	Old/F	mRNA-1273	2nd	2 weeks	NA	Positive	S, PE, IVCY	NA	7.8/NA (mg/dL)	1.9/NA (g/gCr)
6	70/F	NA	2nd	9 days	No	> 350	S, PE, IVCY	1	3.2/< 2.0 (mg/dL)	1.8/NA (g/day)
7	26/M	mRNA-1273	2nd	2 days	Yes	550.0 RR < 7.0	S, PE, POCY	NA	641/HD (μmol/L)	NA
11	69/F	AZD1222	1st	8 weeks	No	584	S, PE, CY	1	1175/HD (μmol/L)	NA
11	72/F	AZD1222	2nd	3 weeks	No	684	S, PE, CY, RIT	1	1200/HD (μmol/L)	NA
Atypical anti-GBM nephritis
10	77/M	BNT162b	1st	1 week	NA	NA	S, MMF	1.5	1.8/2.9 (mg/dL)	1.6/0.3 (g/day)
Current	57/F	BNT162b	1st	11 days	No	2.9 RR < 7.0	S, MZR	14	0.85/1.85 (mg/dL)	7.2/1.3 (g/gCr)

Cr, creatinine; CY, cyclophosphamide; F, female; FU, follow-up; GBM, glomerular basement membrane; HD, hemodialysis-dependent; IVCY, intravenous cyclophosphamide; M, male; MMF, mycophenolate mofetil; mo, month; MZR, mizoribine; NA, not applicable; PE, plasma exchange; POCY, oral cyclophosphamide; REF, reference; RIT, rituximab; RR, reference range; S, steroid.

Three mechanisms of linear IgG deposition in atypical anti-GBM nephritis have been reported via immunofluorescence studies of renal biopsies, despite the absence of anti-GBM antibodies:^{2, 8} (i) presence of undetectable autoantibodies or antibodies to specific GBM antigens; (ii) presence of monotypic light chains with a physicochemical affinity for GBM, as seen in monoclonal immunoglobulin deposition disease (MIDD); and (iii) deposition of nonspecific proteins due to structural changes in the GBM, as in diabetic nephropathy. The first mechanism seems to be more likely in the present case because immunohistochemistry showed an accumulation of polytypic light chains, pathologies such as MIDD were unlikely, and there were no findings of diabetic nephropathy or idiopathic nodular sclerosis.

Atypical anti-GBM nephritis reportedly may not benefit from immunosuppressive therapy.¹ In a small uncontrolled study of multiple immunosuppressant regimens, four of the six patients who received steroids and cyclophosphamide progressed to end-stage kidney disease (ESKD) or died.¹ However, only one of eight patients who received no treatment, steroids alone, or steroids and mycophenolic acid progressed to ESKD or died. Two patients who received plasmapheresis also developed ESKD.¹ Similarly, another study reported that immunosuppressive treatment was ineffective against SARS-CoV-2 vaccine-induced atypical anti-GBM nephritis.¹⁰ This previous case and ours highlight the importance of the careful administration of immunosuppressive drugs for atypical anti-GBM nephritis, even in post-SARS-CoV-2 vaccine cases.

In conclusion, this case suggests that atypical anti-GBM nephritis may develop earlier than classic anti-GBM disease. Furthermore, immunosuppressive therapy may be ineffective in patients who develop atypical anti-GBM nephritis after vaccination for SARS-CoV-2. Further studies are required to elucidate the pathogenesis of atypical anti-GBM nephritis, establish its treatment, and determine its relationship with vaccines.