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Adenovirus Tubulointerstitial Nephritis Banff IIA Acute Allograft Rejection
Ian W. Gibson
University of Manitoba
Winnipeg, Manitoba, Canada
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Case History
A 54-year old male undergoing peritoneal dialysis for end-stage renal disease due to hereditary
nephritis, received a kidney transplant from a living unrelated donor. The donor was a 2-antigen match
(1A, 1DR) and the crossmatch was negative using flow cytometry. Both donor and recipient were CMV
positive. The recipient was treated with prednisone, mycophenolate (1 g bid), and tacrolimus, with the
last of these being started one week prior to transplantation; he did not receive
induction/anti-lymphocyte antibody therapy. The transplant surgery was uncomplicated, and renal function
was immediate; no dialysis was required post-transplant, and the patient's serum creatinine dropped to
156 umol/L (1.76 mg/dl) at one week.
On post-transplant day 2, he complained of odynophagia, and underwent an upper GI endoscopy, which
revealed a ring of discrete ulcers in the lower esophagus, suggestive of viral esophagitis. Biopsies
were taken, and the patient was started on valganciclovir 450 mg bid, following which his symptoms
quickly improved. The esophageal biopsy showed ulcerated squamous mucosa with regenerative changes,
negative for viral inclusions and fungal organisms. Viral cultures and immunocytochemical stains for HSV
and CMV from the esophageal biopsy were both ultimately negative. The patient was maintained on
valganciclovir at the same dose, in addition to his immunosuppression.
He was noted to have viral cytopathic changes ("decoy cells") in his urine on routine monitoring at 12
days post-transplant, and these changes persisted. Weekly serum PCR for BK and JC viruses were negative
throughout the post-transplant course.
An ultrasound of his allograft, performed 2 weeks post-transplant due to persistently high serum
creatinine (around 150-170 umol/L), was suggestive of renal artery stenosis. A conventional renal
angiogram was then performed, which showed no stenosis.
Serum creatinine steadily increased to 190 umol/L (2.15 mg/dl). The patient was clinically well,
repeat ultrasound of the allograft was normal. Acute rejection was suspected, and the patient was given
an oral dose of 200 mg of prednisone, followed by a taper. A renal allograft biopsy was performed three
days later, at six weeks post-transplant (biopsy 1).
One week later, serum creatinine had risen to 283 umol/L (3.2 mg/dl), and a repeat renal allograft
biopsy was performed at seven weeks post-transplant (biopsy 2).
Slide 1
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Slide 2
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Renal Allograft Biopsy no.1
Biopsy 1 - Figure 1
Focal severe tubulointerstitial inflammation, peritubular capillaritis (Banff score ptc3), tubulitis and tubular epithelial injury (H&E). |
Biopsy 1 - Figure 2
Severe tubulointerstitial inflammation, tubulitis (Banff score t3) and tubular epithelial injury with denuded tubular basement membrane (H&E). |
Biopsy 1 - Figure 3
Severe tubulointerstitial inflammation, tubulitis (Banff score t3) and tubular epithelial injury, with tubular mitotic figure (H&E). |
Biopsy 1 - Figure 4
Severe tubulointerstitial inflammation, tubulitis (Banff score t3) and tubular epithelial injury (H&E). |
Biopsy 1 - Figure 5
Severe tubulointerstitial inflammation and edema, and focus of intimal arteritis with subendothelial mononuclear cell infiltration, Banff score v1 (H&E). |
Biopsy 1 - Figure 6
Nodular area of granulomatous interstitial inflammation surrounding injured tubules (H&E). |
Biopsy 1 - Figure 7
Dense interstitial infiltrate with activated lymphohistiocytic cells (H&E). |
Biopsy 1 - Figure 8
Palisading epithelioid cell granuloma surrounding tubule with tubulitis, severe tubular necrosis and smudgy intranuclear inclusions (H&E). |
Biopsy 1 - Figure 9
Tubule with enlarged hyperchromatic smudgy intranuclear inclusion bodies and tubular cell necrosis (H&E). |
Biopsy 1 - Figure 10
Tubule with enlarged hyperchromatic smudgy intranuclear inclusion bodies (H&E). |
Biopsy 1 - Figure 11
Positive tubular nuclear staining for adenovirus DNA (in situ hybridization performed by Dr P. Randhawa, University of Pittsburgh Medical Centre) |
Renal Allograft Biopsy no.2
Biopsy 2 - Figure 5
Moderate acute transplant glomerulitis, with mononuclear cells and neutrophils, Banff score g2 (H&E). |
Biopsy 2 - Figure 6
Moderate acute transplant glomerulitis, with mononuclear cells and neutrophils, Banff score g2 (PAMS). |
Biopsy 2 - Figure 7
Severe peritubular capillaritis with predominantly mononuclear cells, Banff score ptc3 (H&E). |
Findings
Renal Allograft Biopsy no.1 (Figs 1-11)
Two cores were obtained, consisting of renal cortex and medulla with up to 9 glomeruli (including 1
globally sclerosed) and 3 arteries. A severe granulomatous interstitial nephritis was observed, with
palisading tubulocentric granulomas as well as severe tubular epithelial injury with regeneration and
viral cytopathic changes, with enlarged hyperchromatic and smudgy nuclear inclusions. Severe lymphocytic
tubulitis, diffuse severe peritubular capillaritis with mononuclear cells and marginating neutrophils and
a focus of mild intimal arteritis without fibrinoid injury were also seen, consistent with acute
rejection (Banff grade IIA, Banff scores - g0, i3, t3, v1, ptc3, cg0, mm0, ci0, ct0, cv0, ah0).
Stains for AFBs and fungal organisms were negative. Immunocytochemical staining of a paraffin section
for C4d was negative in glomeruli and peritubular capillaries. Immunocytochemical studies showed that
the interstitial infiltrate was a mixture of CD3+ T cells, CD79a+ B cells and CD68+ macrophages, with
some scattered CD20+ B cell aggregates. Immunocytochemical stains for SV40, CMV, HSV and adenovirus
(ADV) were all negative, as was in situ hybridization for BKV, JCV and EBV.
In situ hybridization for ADV DNA (performed by Dr P. Randhawa, University
of Pittsburgh Medical Centre) was positive, with nuclear staining observed in a single cortical distal
tubule, confirming adenovirus infection as the cause of the severe granulomatous interstitial nephritis.
Urine for viral culture grew ADV.
Because of the possibility of an antibody-mediated rejection, based on the finding of vasculitis and
peritubular capillaritis, he was treated with IVIG at a dose of 0.4 mg/kg for four doses; he also
received solumedrol 50 mg IV with each dose, and his mycophenolate was withheld. His valganciclovir was
also discontinued at this time. Serum for donor-specific antibody (DSA) was negative.
One week later, serum creatinine had risen to 283 umol/L (3.2 mg/dl), and a repeat renal biopsy was
performed (biopsy 2).
Renal Allograft Biopsy no.2 (Figs 1-7)
This second biopsy had up to 14 glomeruli (including 1 globally sclerosed) and 2 arteries. There was
ongoing acute tubulointerstitial rejection (Banff grade IB) with moderate acute transplant glomerulitis
(mononuclear cells and neutrophils), severe interstitial inflammation, severe lymphocytic tubulitis with
focal TBM disruption and diffuse severe peritubular capillaritis with mononuclear cells and occasional
neutrophils (Banff scores - g2, i3, t3, v0, ptc3, cg0, mm0, ci0, ct0, cv1, ah1). There was a focus of
arteriolitis with marginating mononuclear cells, but no evidence of intimal arteritis. On this biopsy,
there were no viral cytopathic changes, and there was no granulomatous interstitial inflammation.
Immunocytochemical staining of a paraffin section for C4d remained negative. Immunocytochemical
studies showed the majority of the interstitial inflammation to be CD3+ T cells, with a population of
CD68+ macrophages and a minority of CD20+ B cells. Cells infiltrating glomeruli included CD68+ and CD3+
cells.
In view of the features of acute tubulointerstitial rejection, the patient received a second pulse of
oral steroids (prednisone 200 mg, 150 mg, and 100 mg daily, followed by a taper of 10 mg/day), and his
mycophenolate was restarted at a dose of 250 mg bid, achieving mycophenolic acid trough levels of 1.0-1.5
mg/l. His serum creatinine slowly improved back to the 140-160 umol/l range. Urine cytology continued
to show viral cytopathic changes, and urine culture for ADV remained positive until 3 months
post-transplant, when it became negative.
Renal Allograft Biopsy no.3
At 3 months post-transplant, the patient underwent a third renal allograft protocol biopsy. This
biopsy had up to 11 glomeruli and 2 arteries. It showed no signs of either acute rejection or viral
cytopathic changes, and was essentially normal (Banff scores: g0, i0, t0, v0, ptc0, cg0, mm0, ci0, ct1,
cv1, ah0). Immunofluorescence staining for C4d showed patchy glomerular capillary loop C4d (1-2+), but
peritubular capillaries were C4d negative.
At 6 months post-transplant, the patient remained well with a stable serum creatinine of 130-140
umol/L, and remained on tacrolimus, mycophenolate and prednisone. His urine remained positive for decoy
cells at that time, but urine culture was negative for ADV, and serum PCR for BKV was also negative.
Renal Allograft Biopsy no.4
A protocol allograft biopsy at 6 months post-transplant had up to 10 glomeruli (including 1 globally
sclerosed) and 2 arteries. There was mild tubulointerstitial inflammation (Banff borderline; g0, i1, t1,
v0, ptc0), mild patchy tubular atrophy and interstitial fibrosis (affecting approx. 10% of cortex) and
moderate intimal fibrosis (Banff chronic scores: cg0, mm0, ci1, ct1, cv2, ah0).
The patient is now 24 months post-transplant, with a stable serum creatinine of 130 umol/L (1.47
mg/dl).
Differential Diagnoses:
Granulomatous tubulointerstitial nephritis with allograft viral infection,
adenovirus versus BKV. Acute allograft rejection
Final Diagnosis:
Biopsy 1: Adenovirus tubulointerstitial nephritis Banff IIA acute allograft
rejection
Biopsy 2: Banff IB acute allograft rejection with transplant glomerulitis
Case Discussion:
Viral infections are an increasingly important complication of solid organ transplantation. While the
advent of intensified immunosuppressive protocols has led to lower rates of acute rejection,
opportunistic viral infections such as polyomavirus (typically BKV) are increasingly
recognized [1], and screening programs for viral cytopathic changes (i.e. "decoy cells") are
standard of care [2].
In this particular case, a renal transplant patient developed adenovirus (ADV) infection of his renal
allograft six weeks post-transplant, with allograft biopsy showing a severe granulomatous interstitial
nephritis, severe tubular injury and viral cytopathic changes. Asymptomatic ADV viremia is not uncommon
in solid organ transplant recipients, but active infection within the renal allograft is a rare
complication, usually occurring in the first 6 months post-transplant. At least seventeen cases of renal
allograft infection with ADV have been previously reported in adults
[3,
4,
5,
6,
7,
8,
9,
10,
11,
12,
13,
14],
and one case in a
pediatric renal transplant recipient [15].
ADV is a non-enveloped, double-stranded DNA virus. It is most frequently ADV subgroup B, serotypes 7,
11, 34 and 35 that cause clinical infections in transplant patients, with subtype 11 most commonly
affecting the urinary tract
[13,
16].
Bladder involvement with hemorrhagic cystitis is more
frequent than ADV nephritis. Systemic disease can occur, with possible involvement of GI tract, lung and
liver. A case of fatal disseminated adenovirus infection in a renal transplant recipient has been
described [17]. ADV nephritis in the native kidney and hemorrhagic cystitis have also been
reported in hematopoietic stem cell transplantation [18],
in HIV infection [19]and
post-bone marrow transplantation for Hodgkin's disease [20].
The main differential diagnosis in a renal allograft biopsy is polyomavirus infection. The tubular
viral cytopathic features of ADV replication, with hyperchromatic ground glass or smudgy intranuclear
inclusions (Cowdry A), are similar to the type I inclusions of BKV, but are usually more pronounced in
ADV, with associated severe tubular epithelial necrosis, inflammatory infiltration, tubular basement
membrane disruption and frank tubular destruction.
Severe necrotizing granulomatous tubulointerstitial nephritis with palisading tubulocentric granulomas
surrounding severely injured and virally infected tubules appears to be characteristic of ADV
infection
[3,
5,
6,
8,
13].
The distal nephron is primarily affected, with interstitial nephritis
maximal in the medulla and at the corticomedullary junction
[6,
13].
Necrotizing interstitial
nephritis without granulomas can occur [11], and there is the possibility of a space occupying
lesion in the allograft
[11,
20].
Granulomatous interstitial nephritis, with non-necrotizing
epithelioid granulomas surrounding injured tubules, has rarely been reported in BKV-associated allograft
nephropathy [21]. Other potential causes of granulomatous interstitial nephritis, including
drug-induced, sarcoidosis, ANCA-associated vasculitis, tuberculosis and fungal infections must be
excluded.
Focal wedge-shaped parenchymal necrosis, neutrophils polymorph infiltrates, tubular red blood cell
casts and focal interstitial hemorrhage are seen with ADV and are not typical for other allograft viral
infections [22]. In one case, an immune complex-mediated (presumed postinfectious)
glomerulonephritis developed subsequent to ADV allograft nephritis [13].
Diagnosis can be confirmed with immunocytochemical staining or in situ
hybridization for ADV antigens, showing tubular nuclear staining and possibly weaker cytoplasmic
staining. With electron microscopy, closely packed crystalline arrays of hexagonal ADV particles of
approximately 70-80nm are found in tubular nuclei and cytoplasm [11]. Free virions can be
detected in the urine ultrastructurally using negative staining techniques [22].
There are a number of features that make this case of ADV allograft infection noteworthy. The first
distinctive clinical feature is that, whilst there was graft dysfunction, the patient was essentially
asymptomatic at the time of presentation. In particular, he did not have hematuria or other symptoms of
hemorrhagic cystitis, and he had no systemic symptoms such as fever. It is likely that the esophageal
ulceration at 2 days post-transplant was a viral esophagitis, and symptoms resolved with antiviral
therapy (valganciclovir), but this was not definitively proven to be caused by ADV. The patient was
still receiving antiviral medication, and was on the recommended treatment dose of valganciclovir (900
mg/day) for his level of renal function, yet despite this antiviral medication he still developed ADV
infection in the allograft.
In the previously reported cases of ADV allograft infection
[3,
4,
5,
6,
7,
8,
9,
10,
11,
12,
13,
14,
15],
in addition to allograft
dysfunction, all cases have presented with hemorrhagic cystitis and hematuria and /or fever. In
contrast, the earliest sign of ADV infection in the allograft in this case was the presence of viral
inclusion-bearing epithelial cells identified by urine cytology ("decoy cells"). This case demonstrates
that renal allograft ADV infection may present solely with graft dysfunction and urinary "decoy cells",
thus mimicking polyomavirus infection. Whilst in most cases, "decoy cells" are associated with BKV, and
ADV infection of the renal allograft is a much rarer occurrence, ADV should be included in the
differential diagnosis of any patient with positive urine cytology for viral inclusion bodies.
A further notable feature of this case was the presence of concomitant acute rejection pathology and
ADV infection in the allograft. Acute rejection in association with polyomavirus infections of the
allograft is well recognized [23]. The presence of simultaneous BKV infection and acute
tubulointerstitial rejection pathology complicates the diagnosis and treatment of both processes. The
clinical management of such cases, in particular use of corticosteroid boluses, has been
controversial [24]. It is generally (but not universally) accepted that acute rejection can be
diagnosed with concomitant polyomavirus infection, if there are tubulointerstitial rejection changes in a
biopsy which are clearly separate from areas of tubular viral infection (as demonstrated with SV40
immunostain), if there is an intimal arteritis lesion diagnostic of vascular rejection, or if there is
C4d+ staining in peritubular capillaries indicating a humoral rejection process (consensus guidelines
from Banff 2009 Conference on Allograft Pathology).
There is a recent case report from Japan of acute humoral rejection in an ABO-incompatible renal
allograft with concomitant ADV infection [14], with both acute rejection changes and active ADV
infection identified in the graft nephrectomy. The significance and clinical management of acute
rejection pathology in association with ADV infection in an allograft biopsy is problematic. In this
present case, there was a focus of intimal arteritis as well as severe tubulitis and peritubular
capillaritis in the 1st allograft biopsy, which was strongly suggestive of acute allograft rejection in
addition to ADV infection. Furthermore, the repeat biopsy one week later demonstrating persisting
tubulointerstitial inflammation, acute transplant glomerulitis and severe peritubular capillaritis
without viral cytopathic changes further supports the diagnosis of acute rejection. There is the
possibility that viral infections could be the trigger for an acute rejection process [25].
Treatment strategies for ADV allograft infection include reduction of immunosuppression, IVIG and
specific antiviral therapy. Rapid clearing of the virus, recovery of allograft function and good
long-term graft survival are described
[3,
5,
6,
7,
11],
although some cases have led to rapid graft
loss [14],
and there is the possibility of fatal outcome
[17,
26,
27].
This patient
received an initial steroid pulse for suspected rejection, followed by a reduction in immunosuppression
for confirmed ADV infection, followed by yet another steroid pulse and IVIG for biopsy-proven rejection,
and lastly a more sustained reduction in immunosuppression to assist with clearing of the virus. The
patient improved with an overall reduction in immunosuppression, though co-existent rejection complicated
his course, and the optimal treatment of this clinical scenario is unclear. The essentially normal
allograft biopsy at 3 months, 6 weeks after the first biopsy, demonstrated a remarkable histological as
well as functional recovery from both ADV and/or rejection-related inflammatory injury, and the graft
remains clinically stable at 24 months post-transplant.
Conclusion(s):
This case shows a severe granulomatous tubulointerstitial nephritis in an allograft
caused by adenovirus infection. There is concomitant vascular and severe tubulointerstitial acute
allograft rejection. The patient was treated for acute rejection and with sustained reduction of
immunosuppression to clear the virus. There was rapid resolution of allograft inflammation and good
graft function at 2 years post- transplant.
References:
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