Steroid resistant nephrotic syndrome with collapsing focal segmental glomerulosclerosis in a 12-year-old Japanese female after SARS-CoV-2 vaccination

The Case

A 12-year-old female was referred to our hospital because of severe edema. She had no specific past or family history, including prior infection. School-based urine screening had never detected any abnormalities. Two days after initial administration of the BNT162b2 (Pfizer/BioNTech) vaccine, edema began to gradually appear, and 8 days after the injection, her body weight had increased by 7 kg. Physical examination showed no purpura or arthralgia. Blood test showed severe hypoalbuminemia but no kidney dysfunction or hypocomplementemia (Table 1). Spot urinalysis showed nephrotic range proteinuria (urine protein to creatinine ratio: 12.8 g/gCr) and microhematuria, indicating nephrotic syndrome (NS). The screening polymerase chain reaction test for severe acute respiratory syndrome coronavirus (SARS-CoV-2) was negative. After admission, an albumin infusion was given as supportive treatment. Twenty-one days after vaccination and before initiating steroid treatment, kidney biopsy was performed. Light microscopy study (periodic acid-Schiff stain) revealed mesangial consolidation and loss of endocapillary patency and extracapillary epithelial proliferation, which is consistent with focal segmental glomerulosclerosis (FSGS) collapsing variant (Fig. 1A–C) [1]. Electron microscopy showed foot process fusion, but no tubuloreticular inclusions (Fig. 1D). Treatment with prednisolone 60 mg/m²/day with an upper limit of 60/mg/day was started according to clinical guidelines on childhood NS. Twenty-eight days after initiation of prednisolone, the patient had not achieved complete remission, so we started cyclosporine treatment and lisinopril therapy. Two cycles of methylprednisolone pulse therapy (1000 mg for 3 days) were also administered. Complete remission was finally achieved after 10 weeks of treatment (Table 1) with no adverse events. Comprehensive genetic testing with targeted sequence panel by next generation sequencing revealed no gene variants causing steroid-resistant NS or asymptomatic proteinuria (sTable 1) [2]. Human immunodeficiency virus (HIV) testing was not performed because of the low probability of infection. After complete remission, prednisolone was tapered, and therapy with cyclosporine and lisinopril was continued. At the last observation (6 months later), eGFR tended to be lower compared with values at the beginning of the disease. It is impossible to determine whether this is the effect of cyclosporine or the progression of the underlying disease. Follow-up renal biopsy is scheduled for 2 years after the start of treatment.

Table 1.

Laboratory Findings

Laboratory results					Urinalysis
	On admission	10 weeks after treatment	At 6-month follow up			On admission	10 weeks after treatment	At 6-month follow up
WBC	9700	6900	10,200	/μL	Blood	3 +	–	–
Hb	14.9	13.7	11.8	g/dL	RBC	> 100	14	15	/hpf
Hct	42.3	40.7	34.1	%	protein	4 +	–	–
Plt	49.9	40.9	37.2	104/μL	Protein/Cr	12.8	0.11	< 0.03	g/gCr
CRP	0.01	< 0.01	< 0.01	mg/dL
AST	32	13	14	U/L
ALT	30	10	8	U/L
LDH	276	196	170	U/L
Na	136	139	139	mmol/L
K	4.9	4.7	4	mmol/L
BUN	12.8	8.6	13.3	mg/dL
Cr	0.45	0.44	0.51	mg/dL
eGFR	118	120	103	ml/min/1.73m2
TP	4.1	6.3	6.5	g/dL
Alb	1.4	4.2	4.3	g/dL
T-Chol	542	225	190	mg/dL

hpf high-power field, eGFR estimated glomerular filtration rate

Fig. 1.

A Light microscopy study (periodic acid-Schiff stain, original magnification × 80) showed mild mesangial proliferation and collapsing variant of focal segmental glomerulosclerosis (FSGS) in two of 38 glomeruli (one glomerulus with FSGS is surrounded by a black square). B, C The glomeruli with FSGS findings (periodic acid-Schiff stain, original magnification × 400). These are collapsing variant of focal segmental glomerulosclerosis characterized by tuft collapse and overlying epithelial hypertrophy, and hyperplasia accompanied by mesangial proliferation. D Ultrastructural examination (original magnification × 4000) reveals extensive foot process effacement without tubuloreticular inclusions

Lessons for the clinical nephrologist

Renal side effects may appear after vaccination against SARS-CoV-2 infection [3]. Nephrotic syndrome following vaccination is a novel concern in the current pandemic era. Pathologically, most cases of NS after vaccination are associated with minimal change disease or FSGS. All previous reports have focused upon adult patients, however, and owing to fundamental differences between onset mechanisms of NS in adults and children, the situation may differ in children [4]. The actual mechanism has not yet been elucidated, but the immunological impact is reported to be associated with onset after vaccination. Pathologically, minimal change disease has been predominantly reported, followed by acute tubulointerstitial inflammation, FSGS, or others, such as membranous nephropathy and IgA nephropathy [4]. The FSGS collapsing variant found in this patient is known to be associated with secondary FSGS [5]. HIV is the most commonly-reported cause of FSGS collapsing variant, known as HIV-associated nephropathy (HIVAN) [6]. This is closely related to the APOL1 risk variants that have been observed and reported in individuals of African ancestry [6]. Activation of cytokine and interferon, as well as viral gene expression such as Nef, Vpr, Tat and APOL1 risk allele expression, is thought to be the most common etiology of HIVAN [7]. Similar to HIVAN, SARS-CoV-2 has also been reported as a cause of COVID-19-associated nephropathy (COVAN) [8]. SARS-CoV-2 infection is reportedly associated with FSGS collapsing variant, mainly in patients with the APOL1 variant (sTable2). Our patient was only vaccinated, not infected, and is of Japanese and not African ancestry, so she is unlikely to have had the APOL1 risk variant, but there may be common etiology. It is a limitation of this case that the existence of the APOL1 variant was not examined. Tubuloreticular inclusions, known evidence of interferon activation, have been reported in patients with HIVAN and COVAN, but they were not apparent in our patient (Fig. 1D) [9]. The patient had complete remission after responding well to prednisolone and immunosuppressive treatment, and is doing well with no renal insufficiency (Table 1). The short time between vaccination and symptom onset, and the fact that a kidney biopsy 21 days later already showed collapsing FSGS, is similar to the course of COVAN. However, the extent of collapsing FSGS was no more extensive than that of previously reported COVAN cases and may be related to better treatment response in this patient. Collapsing FSGS may appear after SARS-Cov-2 vaccination in children, but further evidence of the link is required.

Supplementary Information

Below is the link to the electronic supplementary material.

Data availability

Data from this study can be obtained from the corresponding author on reasonable request.

Declarations

Conflict of interest

The authors of this manuscript have no relevant financial or non-financial interests to disclose. No funds, grants, or other support has been received.

Ethical statement

The authors declare that they have obtained consent from the patient’s parents for publication of information that appears within this article.

Prior presentation

A first version of this work were submitted in Abstract form to the American Society of Nephrology Kidney Week meeting in November 2022.