EBV Mononucleosis: Nephrotic Syndrome & Tubulointerstitial Nephritis in Child

Case report
Concomitant nephrotic syndrome and
tubulointerstitial nephritis in a child with Epstein-­Barr
virus mononucleosis
Ratna Acharya,1 Xu Zeng,2 Kiran Upadhyay ‍ ‍3
1
Pediatrics, University of Florida,
Gainesville, Florida, USA
2
NephroPathology, University
of Florida College of Medicine,
Gainesville, Florida, USA
3
Pediatrics, Nephrology,
University of Florida Health,
Gainesville, Florida, USA
Correspondence to
Dr Kiran Upadhyay;
​dockiranbp@​yahoo.​com
Accepted 23 January 2021
SUMMARY
Acute kidney injury (AKI) and nephrotic syndrome (NS)
are uncommon manifestations of Epstein-­Barr virus
(EBV) mononucleosis. We report a 4-­year-­old boy with
Infectious mononucleosis (IM) who presented with
dialysis-­requiring AKI and NS. Renal biopsy showed
severe acute tubular necrosis, mild chronic interstitial
nephritis and focal podocyte foot processes effacement.
EBV early RNA was not detected in the renal tissue.
However, immunophenotyping of peripheral lymphocytes
showed increased cytotoxic T cell activity and increased
memory B cells. Treatment with steroid led to rapid
resolution of NS within 3 weeks. Renal function
stabilised. EBV viral capsid antigen (VCA) IgM remained
elevated until 4 months before starting to decline when
VCA IgG and nuclear antigen started appearing. B
lymphocytes are the predominant target cells in EBV
infection and additionally may also act as antigen
presenting cells to T lymphocytes, thereby eliciting the
strong immune response and leading to podocyte and
tubulointerstitial injury.
BACKGROUND
In children, primary Epstein-­
Barr virus (EBV)
infection is the most common cause of Infectious
mononucleosis (IM) and is manifested by fever,
acute pharyngitis, cervical lymph node swelling,
and hepatosplenomegaly. Renal involvement is
uncommon but may present as tubulointerstitial
nephritis (TIN) leading to proteinuria, haematuria
and/or acute kidney injury (AKI).1 Rarely, nephrotic
syndrome (NS) can occur in association with EBV.2 3
Here, we report an unusual concomitant occurrence
of minimal change glomerulonephritis with podocyte foot process effacement and AKI secondary to
IN and acute tubular necrosis (ATN) in a 4-­year-­old
boy with EBV-­IM.
from his baseline weight. Physical examination was
significant for clear rhinorrhea, bilateral cervical
lymphadenopathy, tonsillar enlargement with
exudates, left otitis media, splenomegaly and generalised anasarca including bilateral scrotal oedema.
Rest of the examination was normal.
INVESTIGATIONS
Heterophile antibody test by immunoassay was
positive. Renal function panel showed a blood
urea nitrogen of 104 mg/dL, serum creatinine 7 mg/
dL (estimated glomerular filtration rate 6 mL/
min/1.73 m2, bedside schwartz equation) with
hyponatraemia, hyperkalaemia and acidosis. Serum
albumin was 2 g/dL. Urinalysis showed 4+ proteinuria, no microscopic haematuria, hyaline and
granular casts. There was no myoglobinuria. First
morning urine protein to creatinine ratio was 6.5
and the urine β2 microglobulin was >20 000 μg/L
(normal:≤300 μg/L). Nasopharyngeal swab PCR for
influenza A H1-2009, coronavirus (229E, HKU1,
NL63 and OC43) was negative; SARS-­CoV-2 was
not tested. Initial serum EBV DNA PCR load was
4.2 million copies/mL. EBV viral capsid antigen
(VCA) IgM was elevated but VCA IgG, early antigen
and nuclear antigen were negative. Other viral
PCRs and serologies were negative. Lupus serology
was negative. Blood and urine cultures were negative. Serum IgM level was elevated and IgG was
low. Blood counts showed mild anaemia but normal
white cell and platelet counts. Absolute lymphocyte
CASE PRESENTATION
© BMJ Publishing Group
Limited 2021. No commercial
re-­use. See rights and
permissions. Published by BMJ.
To cite: Acharya R, Zeng X,
Upadhyay K. BMJ Case
Rep 2021;14:e240108.
doi:10.1136/bcr-2020240108
A previously healthy 4-­
year-­
old Caucasian boy
presented with a 1-­
week history of ear pain,
cough, sore throat and fever. He also had a 3-­day
history of generalised body swelling and decreased
urine output. There was no history of vomiting,
diarrhoea, abdominal pain, urinary frequency,
haematuria, dysuria and usage of non-­steroidal anti-­
inflammatory agents. Medical and family history
was unremarkable.
On examination, the vital signs were stable
except for temperature of 39.05 degree celcius.
There was an interval weight gain of 5 kg (20%)
Figure 1 (A) A glomerulus shows normal mesangial
cellularity (Periodic Acid Schiff (PAS) stain,40×10). (B, C)
Interstitial fibrosis and proximal tubules with flattening
of tubular epithelium, tubular atrophy, and granular casts
in tubular lumen (H&E, 20×10 and 40×10). (D) Interstitial
infiltration with mononuclear cells (H&E).
Acharya R, et al. BMJ Case Rep 2021;14:e240108. doi:10.1136/bcr-2020-240108
1
Case report
situ hybridisation study for EBV early RNA (EBER) in the renal
tissue was negative.
DIFFERENTIAL DIAGNOSIS
EBV mononucleosis-­related AKI and minimal change NS was the
primary diagnosis which was supported by the clinical presentation, positive heterophile test, positive EBV serology and PCR.
Figure 2 Immunohistochemical staining of the renal tubulointerstitial
mononuclear infiltrate with CD3, CD4 and CD8 (A, B and C,
respectively).
and monocyte counts were 5000 cells/µL and 1200 cells/µL,
respectively. Peripheral smear showed 10% atypical lymphocytes. Flow cytometric analysis of peripheral blood showed
increased number of CD3+ T cells (85%), CD8+ T cells (38%)
along with increased CD3+ cells expressing HLA-­DR (69%),
low CD19+ B cells (4%) and increased CD27+ B cells (62%),
the latter indicating memory B cells. CD4/CD8 ratio was 1.07.
Chest X-­ray was normal. Abdominal sonogram showed ascites,
mild hepatomegaly and splenomegaly (10.4 cm). Renal sonogram showed bilateral echogenic enlarged kidneys.
Percutaneous renal biopsy performed on day 2 of hospitalisation showed normal glomerular mesangial cellularity and
absence of segmental sclerosis, necrosis or cellular crescents.
The biopsy sample consisted of two portions of renal cortex and
two portions of corticomedullary tissue with two interlobular
arteries. A total of 17 glomeruli were identified. There was diffuse
denudation and flattening of mostly proximal tubular epithelial
cells with loss of brush border. Some proximal and distal tubules
contained granular casts. There was mild interstitial fibrosis and
focal tubular atrophy. The interstitial inflammation was mild but
focally heavier with mononuclear cells which stained positive
with CD3, and also for both CD4+ and CD8+ T cells (figures 1
and 2). Hence, in addition to ATN, there was evidence of chronic
IN as well. Immunofluorescence showed diffuse, pseudolinear
staining in glomerular capillary loops for albumin. There was no
specific glomerular staining noted for IgG, IgA, IgM, C3, C1q,
kappa light chain or lambda light chain. Electron microscopy
showed mostly intact podocyte foot processes with only focal
effacement, and absence of electron-­dense deposits (figure 3). In
Figure 3 Electron microscopy. Arrows showing focal foot process
effacement of the podocytes with loss of slit-­diaphragms adjacent to
the glomerular basement membrane, magnification ×6000.
2
TREATMENT
Haemodialysis (HD) was initiated for hyperkalaemia, acidosis
and oliguria. He received one dose of 10 mg/kg intravenous
pulse steroid. HD was not required after five sessions. He was
discharged on 2 mg/kg oral prednisone for 6 weeks, followed
by 1.5 mg/kg alternate day prednisone for another 6 weeks with
normalisation of serum albumin and oedema within 3 weeks.
OUTCOME AND FOLLOW-UP
Heterophile antibody test returned negative in 2 months. VCA
IgM was persistently elevated until 4 months before starting
to decline. VCA IgG and nuclear antigen became positive at
4 months. EBV viraemia resolved after 7 months. At his most
recent 8 months follow-­up, he had strong positive IgG antibody
to VCA and nuclear antigen, and negative VCA IgM antibody.
Urine β2 microglobulin remained persistently elevated. Renal
function was stable. SARS-­CoV-2 IgG antibody to N protein was
negative. He has not had any further relapses of NS since the
initial episode.
DISCUSSION
In children, a few reports have described the various manifestations of EBV-­associated nephropathy. A retrospective study of 165
children with primary EBV infection reported an AKI incidence
of 5%, with TIN being the most common renal histology.4 NS in
association with EBV infection was described in a 19-­month-­old
girl who had resolution of proteinuria with abatement of EBV.3
Minimal change disease and collapsing glomerulopathy have
been reported.2 5 A retrospective review of 124 children with
idiopathic NS showed that there is a high prevalence of current
or recent EBV infection at the onset of NS.6
The pathogenesis of renal injury in EBV infection is not well
known. The T cells in patients with EBV-­associated TIN are probably activated by the infiltrating B cells expressing various EBV
antigens. Although the definite causation could not be established
due to the absence of EBER in the renal tissue in our patient, the
temporal relationship between the onset of IM and renal injury
are closely related. Indeed, the EBV genome has been noted in
renal biopsy specimens in some patients, but not all.2 7 Differences
in the sensitivity of the test or low number of EBV RNA may also
cause false negativity. Also, EBV genome in renal tissue has been
found in patients with other conditions such as IgA nephropathy,
among others.8 The elevated initial serum EBV PCR and positive
VCA IgM antibody at the time of presentation further suggests a
probable association. The presence of cytotoxic T cells along with
the helper T cells in the renal tissue of our patient also indirectly
supports the evidence of host defence mechanism in response to
the viral injury. In an immunocompetent host, the EBV-­specific T
cells, mainly HLA class-­I restricted CD8+ cells, along with innate
cells play a major role in controlling the virus.9 These cytotoxic
CD8+ T cells are highly activated, expressing HLA-­DR3 among
others.9 In our patient, there were increased numbers of CD8+
T cells and the Human Leukocyte Antigen (HLA)-­DR CD3+ T
cells. The activated CD8+ T cells kill the infected cells via secretion of cytokines, production and release of cytotoxic granules
Acharya R, et al. BMJ Case Rep 2021;14:e240108. doi:10.1136/bcr-2020-240108
Case report
and via Fas/FasL interactions.9 CD4+ T cells also get activated
to some extent, as seen in our case, since they recognise peptides
presented on MHC class II molecules found on B cells.
Becker et al detected the EBV genome in the renal proximal
tubular cells (PTC) along with the CD21, the receptor for EBV,
in patients with IN.10 Hence, ATN in our patient could be due to
EBV infection of PTC which evoked cellular immune response
that resulted in a prolonged tubular and interstitial injury leading
to AKI and prolonged tubular proteinuria.
With regard to albuminuria and NS, viral infections are
known to alter the podocyte structure and function.11 In addition, systemic T cell dysregulation occurs in NS, which directly
damage the glomerular basement membrane and podocytes or
produce cytokines capable of altering the permeability of the
filtration barrier.12 This was supported by the fact that the initiation of steroid led to rapid normalisation of serum albumin and
oedema. Besides anti-­inflammatory action, steroids are known
to directly regulate podocyte morphology and function, prevent
podocyte apoptosis and stabilise the podocyte actin filament.12
EBV-­infected memory B cells, which are abundant in the peripheral memory compartment during acute EBV infection, have
been shown to be present at the onset of NS; this was also seen
in our case.13 Besides acting as antigen presenting cells to activate T cells and cytokine production to modulate inflammatory
response, activated B cells can also directly cause podocyte foot
processes effacement and proteinuria.13 It was interesting to
see that the podocyte foot process effacement was not diffuse
despite the degree of proteinuria, but was partial. van den Berg
et al showed that the extent of foot process effacement is independent of the degree of proteinuria.14 Also, there may be some
effect of timing as well as some animal models of nephrosis
have shown that the foot process effacement is less severe if
biopsy is performed shortly after onset of proteinuria.15 Our
patient underwent biopsy 2 days after admission and hence this
could have led to the observation of only partial foot process
effacement.
Learning points
►► Epstein-­Barr virus (EBV) mononucleosis can present with
severe acute tubular necrosis and tubulointerstitial nephritis
requiring dialysis.
►► Nephrotic syndrome can occur in association with EBV
infection.
►► EBV genome may not always be detected in the renal tissue
despite renal injury.
►► Steroid treatment may be beneficial in reversing the renal
function and resolution of nephrotic syndrome in EBV-­
associated renal injury.
Acharya R, et al. BMJ Case Rep 2021;14:e240108. doi:10.1136/bcr-2020-240108
This report describes the presence of NS along with tubulointerstitial renal injury in a child with EBV mononucleosis.
Activated T cells due to presence of EBV infected B cells in
renal tissue leading to inflammatory response and/or direct T
or B cell mediated podocyte and tubulointerstitial injury are
possible mechanisms of EBV nephropathy. Further studies are
needed to determine the causal relationship between EBV and
renal injury.
Contributors RA, XZ and KU: collected data, drafted the initial manuscript, and
reviewed and revised the manuscript; KU: collected data, conceptualised the study,
drafted the initial manuscript and critically reviewed and revised the manuscript; all
authors approved the final manuscript as submitted and agreed to be accountable
for all aspects of the work.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
ORCID iD
Kiran Upadhyay http://​orcid.​org/​0000-​0002-​8441-​0220
REFERENCES
1 Okada H, Ikeda N, Kobayashi T, et al. An atypical pattern of Epstein-­Barr virus infection
in a case with idiopathic tubulointerstitial nephritis. Nephron 2002;92:440–4.
2 Joshi A, Arora A, Cimbaluk D, et al. Acute Epstein-­Barr virus infection-­associated
collapsing glomerulopathy. Clin Kidney J 2012;5:320–2.
3 Blowey DL. Nephrotic syndrome associated with an Epstein-­Barr virus infection.
Pediatr Nephrol 1996;10:507–8.
4 Tsai J-­D, Lee H-­C, Lin C-­C, et al. Epstein-­Barr virus-­associated acute renal failure:
diagnosis, treatment, and follow-­up. Pediatr Nephrol 2003;18:667–74.
5 Mikhalkova D, Khanna S, Vaidya R, et al. Epstein-­Barr virus-­associated nephrotic
syndrome. Clin Kidney J 2012;5:50–2.
6 Dossier C, Sellier-­Leclerc A-­L, Rousseau A, et al. Prevalence of herpesviruses at onset
of idiopathic nephrotic syndrome. Pediatr Nephrol 2014;29:2325–31.
7 Lei PS, Lowichik A, Allen W, et al. Acute renal failure: unusual complication of Epstein-­
Barr virus-­induced infectious mononucleosis. Clin Infect Dis 2000;31:1519–24.
8 Sato Y, Furuyama K, Suzuki T, et al. Acute kidney injury in an adult patient with IgA
nephropathy and chronic replicative Epstein-­Barr virus infection. CEN Case Rep
2019;8:285–91.
9 Hoshino Y, Morishima T, Kimura H, et al. Antigen-­Driven expansion and contraction of
CD8+-activated T cells in primary EBV infection. J Immunol 1999;163:5735–40.
10 Becker JL, Miller F, Nuovo GJ, et al. Epstein-­Barr virus infection of renal
proximal tubule cells: possible role in chronic interstitial nephritis. J Clin Invest
1999;104:1673–81.
11 Yamashita M, Millward CA, Inoshita H, et al. Antiviral innate immunity disturbs
podocyte cell function. J Innate Immun 2013;5:231–41.
12 Colucci M, Corpetti G, Emma F, et al. Immunology of idiopathic nephrotic syndrome.
Pediatr Nephrol 2018;33:573–84.
13 Hochberg D, Souza T, Catalina M, et al. Acute infection with Epstein-­Barr virus targets
and overwhelms the peripheral memory B-­cell compartment with resting, latently
infected cells. J Virol 2004;78:5194–204.
14 van den Berg JG, van den Bergh Weerman MA, Assmann KJM, et al. Podocyte
foot process effacement is not correlated with the level of proteinuria in human
glomerulopathies. Kidney Int 2004;66:1901–6.
15 Orikasa M, Matsui K, Oite T, et al. Massive proteinuria induced in rats by a single
intravenous injection of a monoclonal antibody. J Immunol 1988;141:807–14.
3
Case report
Copyright 2021 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit
https://www.bmj.com/company/products-services/rights-and-licensing/permissions/
BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission.
Become a Fellow of BMJ Case Reports today and you can:
►► Submit as many cases as you like
►► Enjoy fast sympathetic peer review and rapid publication of accepted articles
►► Access all the published articles
►► Re-use any of the published material for personal use and teaching without further permission
Customer Service
If you have any further queries about your subscription, please contact our customer services team on +44 (0) 207111 1105 or via email at [email protected].
Visit casereports.bmj.com for more articles like this and to become a Fellow
4
Acharya R, et al. BMJ Case Rep 2021;14:e240108. doi:10.1136/bcr-2020-240108