Case 1 -
1) BK-Polyomavirus Nephropathy, Stage A
2) Acute Tubulo-interstitial Cellular Rejection (Banff '97: Type IB, C4d Negative)
University of North Carolina
Chapel Hill, NC
Click on each slide thumbnail image for an enlarged view
The patient is a 39-year-old African American male who had developed end stage renal disease
(presumably secondary to hypertension). He had been on hemodialysis for more than 5 years. In August
2004 the patient received a renal transplant of cadaveric origin. (A zero-hour implantation biopsy
revealed only unremarkable medullary parenchyma.) The renal allograft functioned reasonably well post
surgery (baseline serum creatinine reading 10 days post transplantation = 1.6 mg/dl). The patient was
enrolled into a "blinded drug trial protocol" with baseline immunosuppression consisting of
cysclosporine, prednisone and a study drug (either mycophenolate mofetil or FTY720). During the first 2
months after surgery, he experienced a complicated clinical course with wound dehiscence and infection
requiring surgical intervention and antibiotic therapy.
Case 1 - Figure 1 - Low power magnification of the renal cortex with unremarkable glomeruli and a patchy inflammatory cell infiltrate in the interstitial compartment. H&E stained section, 4x original magnification.
Case 1 - Figure 2 - Low power magnification of the renal cortex with unremarkable glomeruli and a patchy inflammatory cell infiltrate in the interstitial compartment. H&E stained section, 4x original magnification.
Case 1 - Figure 3 - Renal cortex with unremarkable glomeruli and a patchy infilammatory infiltrate in the interstitial compartment. 20x original magnification; PAS stained sections, 10x original magnification.
Case 1 - Figure 4 - There is interstitial inflammation and some tubulitis. 20x original magnification.
Case 1 - Figure 5 - Interstitial fibrosis is inconspicuous. Trichrome stained section.
Case 1 - Figure 6 - The tubulo-interstitial compartment shows focal edema and inflammatory cell infiltrates composed of mononuclear cell elements and scattered plasma cells. Some non-atrophic tubules show marked tubulitis. 40x original magnification.
Case 1 - Figure 7 - The nuclei of tubular epithelial cells show structural irregularities possibly representing intranuclear polyomavirus inclusion bodies (types 2 and 3). Suboptimal tissue processing resulted in nuclear artifacts precluding a definitive assessment. H&E stained section, 100x original magnification.
Case 1 - Figure 8 - Immunohistochemical incubation to detect the SV-40T antigen (i.e. the "pan-polyomavirus antigen"). The interstitial compartment shows a diffuse inflammatory cell infiltrate and focal tubulitis; only very rare individual tubular epithelial cells reveal a positive (brown) intranuclear staining reaction. 10x original magnification.
Case 1 - Figure 9 - Immunofluorescence microscopy to detect the complement degradation product C4d. C4d is not detected along peritubular capillaries. (C4d is noted in the mesangial region of a glomerulus. This is a non-diagnostic finding which serves as a convenient internal staining control). 20x original magnification.
Case 1 - Figure 10 - Immunofluorescence microscopy to detect tubular epithelial MHC-class II (HLA-DR) expression. Tubular epithelial cells/tubules focally upregulate class II. (Peritubular and glomerular capillaries constantly express class II; this endothelial staining pattern serves as a convenient internal staining control.) 20x original magnification.
| 8/04 || 1.6 mg/dl|
| 9/04 || 2.3 mg/dl|
| 10/04 || 2.6 mg/dl|
| 11/04 || 2.3 mg/dl|
| No hematuria or proteinuria |
| Urine cytology ||8/04|
| no decoy cells |
no decoy cells
40 - 100 decoy cells / 10 high power fields
| Urine PCR || 10/04 || 200.000.000 BK-virus copies/ml|
| Serum PCR || 8/04 - 11/04 |
| no detection of CMV or EBV |
600 BK-virus copies / ml serum
Unsuccessful biopsy attempts end of October; diagnostic graft biopsy 11/18/2004.
Renal Biopsy Findings
- Light Microscopy
The biopsy consisted of 1 tissue core showing renal cortex with 30 unremarkable glomeruli. The
interstitial compartment revealed focal mild edema and a patchy (35%) inflammatory cell infiltrate
composed of mononuclear cell elements, plasma cells and scattered rare eosinophilic leukocytes. Some
tubules showed marked lymphocytic tubulitis or mild atrophy with thickening of the TBM. Interstitial
fibrosis was inconspicuous. Tubular epithelial cells demonstrated reactive nuclear atypia and very focal
irregularities suggestive of intranuclear viral inclusion bodies. Frank tubular epithelial cell necrosis
with denudation of tubular basement membranes were not present. Arterioles and small arteries
demonstrated enlarged endothelial cells but no evidence of transplant endarteritis.
- Immunofluorescence Microscopy/Immunohistochemistry
- Immunofluorescence microscopy: No diagnostically significant deposition of immunoglobulins,
complement factors C1q and C3, and fibrin were found in glomeruli. The complement degradation product
C4d was not detected along peritubular capillaries. Tubules/tubular epithelial cells focally expressed
MHC-class II (HLA-DR).
- Immunohistochemistry: Incubations with a monoclonal antibody directed against the SV40T antigen
("pan-polyomavirus antigen") revealed a positive nuclear staining reaction in tubular epithelial cells
(involving approximately 15% -20% of all tubules).
- Electron Microscopy
- BK-polyomavirus nephropathy, stage A
- Acute tubulo-interstitial cellular rejection (Banff '97: type IB, C4d negative)
Polyomavirus nephropathy, commonly referred to as BK-virus nephropathy (BKN) after the main causative
agent, the BK-polyomavirus strain, was first described as a single case report by the pathologist
Mackenzie in 1978 . In subsequent years, however, during the era of cyclosporine and azathioprine
based immunosuppression, BKN was largely 'forgotten'
. The clinical scenario changed dramatically
in the mid 1990s when new third generation immunosuppressive drugs, specifically, high dose tacrolimus
and mycophenolate-mofetil were introduced into the routine management of kidney transplant recipients in
many centers worldwide
. Interestingly, one of the largest initial series of patients suffering
from BKN was reported from the University of Pittsburgh one of the first transplant centers that had
largely replaced cyclosporine with tacrolimus . Risk factors for BKN, however, are still not fully
understood, and "high dose immunosuppression" with new drugs is likely only one component in a
multi-factorial risk profile promoting viral disease
Currently, BKN is reported with a prevalence of 1% to up to 10% with rising incidence rates
. BKN is by far the most important infectious complication affecting kidney transplants. It
exceeds productive CMV infections of renal allografts by approximately 30 times. Since effective
anti-viral treatment strategies are poorly defined, BKN often leads to severe allograft dysfunction and
. Graft failure rates, especially when BKN is diagnosed late (stages B and C)
and/or treatment strategies fail, can reach 50% to 100% within 24 months following the initial diagnosis
. Improved graft survival has recently been reported from centers with vigorous patient
screening programs which facilitate an early diagnosis of BKN and a better outcome
BKN in renal allograft recipients is typically limited to the transplanted kidney.
Depending on the extent of virally induced tubular injury, patients clinically present with varying
degrees of allograft dysfunction. Serum creatinine levels vary from normal (BKN stage A) to markedly
increased (BKN stages B and C)
. The native kidneys are free of disease and systemic signs of
an infection (fatigue, fever) are generally absent. BK-virus associated hemorrhagic cystitis, often seen
after bone marrow transplantation, is not found in the setting of BKN in renal allograft recipients.
Early observations linking productive infections of BK viruses with ureteral stenosis could not be
confirmed in recent reports
. The definitive diagnosis of BKN requires a kidney biopsy and the
detection of characteristic histologic changes
Two morphologic features define
BKN: i) intranuclear viral inclusion bodies in tubular and parietal (glomerular) epithelial cells, and
ii) virally induced tubular epithelial cell injury and necrosis
. BK viruses use the
proliferative "machinery" of the host cells for replication. The formation of intranuclear viral
inclusion bodies is a characteristic histologic sign of a productive polyomavirus infection, i.e. BKN.
Four distinct variants of viral intranuclear inclusion bodies as well as "hybrid forms" exist which can
often be seen side by side:
|Type 1 (the most frequent form) - an amorphous basophilic ground-glass inclusion body;|
|Type 2 – a central, eosinophilic, granular type surrounded by a (mostly incomplete) clear halo;|
|Type 3 – an eosinophilic finely granular form without a halo; and|
|Type 4 - a vesicular variant with clumped, irregular chromatin and occasional nucleoli
It is currently undetermined whether the different phenotypes of inclusion bodies represent various
stages of intranuclear viral replication and maturation and/or potential fixation artifacts. A
productive infection with polyomaviruses does not induce cytoplasmic inclusion bodies. Ultimately, the
intranuclear viral replication and assembly results in the lysis of the host cell and the release of
mature daughter virions.
The most important histologic changes are seen in the tubules since virally induced tubular
epithelial cell injury and necrosis with denudation of basement membranes are the morphologic correlates
for graft dysfunction in stages B and C
. Of special note: Despite the marked virally
induced epithelial cell damage, the tubular basement membranes remain intact. They can serve as the
structural skeleton for tubular regeneration and healing once the viral replication ceases. Therefore,
BKN, especially stages A and B, can heal with morphologic and functional restitution.
BKN typically involves renal tubules and collecting ducts in a focal fashion. Often,
severely injured tubules containing many inclusion bearing epithelial cells are located adjacent to
normal tubules. This observation may potentially reflect the ascending route of viral spread within
The replication of polyomaviruses is limited to epithelial cell elements. A productive
infection is generally not seen in stromal, mesangial, endothelial, and inflammatory cells or in
podocytes. Occasionally, inclusion bodies are observed in the parietal epithelial cell layer lining
Bowman's capsule and within small "pseudo-crescents"  . Signs of a productive BK virus infection can
also be detected in the transitional cell layer lining the renal pelvis, the ureters and/or the urinary
bladder  . Viral inclusion bodies in transitional cells, however, are not part of the histologic
features that define BKN.
Diagnostic confirmation of BKN is generally achieved by immunohistochemistry, in-situ hybridization
and/or electron microscopy. These techniques are well suited to identify various viral families and
potentially viral strains if a productive viral infection is already suspected by light microscopy.
However, their routine diagnostic use as generalized screening tools to "hunt" for a productive
polyomavirus infection is neither helpful nor cost effective
Histologic stages/patterns of BKN:
BKN can present with different histologic patterns and progress through various
. Three patterns/stages have recently been defined at the "Polyomavirus
Allograft Nephropathy Consensus Conference" (Basel, Switzerland, October 2003, ). They are listed
here with slight modifications:
Pattern/stage A represents the earliest stage of BKN with only scattered intranuclear viral inclusion
bodies likely located in re-activated intra-renal foci of latent BK virus infections. BKN-stage A, in
contrast to stages B and C, responds to therapy more frequently with favorable graft survival and
cessation of viral replication in up to 50% of patients
. Since tubular injury in
pattern A is very limited, (often confined to the renal medulla) graft function typically remains stable,
and the optimal timing of a diagnostic graft biopsy, which is generally triggered by allograft
dysfunction, becomes a clinical challenge. BKN- stage A can progress to stages B or C if productive
viral replication spreads and virally induced tubular injury persists over weeks to months. In one
series, progression was observed in 70% of follow-up graft biopsies . The therapeutic goal of BKN in
stages A and B is to limit viral replication and tubular injury, to promote tubular epithelial cell
regeneration and to prevent disease progression to stage C with irreversible fibrosis and tubular
atrophy. BKN-stage C is typically associated with severe allograft dysfunction or loss
- Pattern/stage A (limited/early stage): Signs of viral replication in
less than 25% of cortical and medullary tubular cross sections with only minimal evidence of epithelial
cell necrosis and denudation of tubular basement membranes. Interstitial inflammation, fibrosis and
tubular atrophy are inconspicuous. Changes classified as pattern/stage A are often most pronounced in
the renal medulla.
- Pattern/stage B (florid, fully developed stage): Signs of viral replication in
more than 10% of cortical and medullary tubular cross sections with conspicuous epithelial cell necrosis,
denudation of tubular basement membranes, and interstitial edema. Inflammation, sometimes rich in plasma
cells and polymorphonuclear leukocytes, is common, whereas interstitial fibrosis and tubular atrophy are
minimal. Changes classified as pattern B can be found in the renal cortex and medulla.
C (late, sclerosing phase): Signs of viral replication in generally less than 25% of cortical and
medullary tubular cross sections associated with tubular epithelial cell injury. Interstitial
inflammation can vary from minimal to marked. Fibrosis and tubular atrophy are typically seen in more
than 25% of the tissue sample. Changes classified as pattern C are frequently most pronounced in the
BKN, interstitial nephritis and rejection:
The correct diagnostic
interpretation of "inflammatory changes" in the setting of BKN can be difficult and has led to
considerable controversy. Often, BKN is simply referred to as "BK-Virus interstitial nephritis".
Although, this descriptive term accurately describes the findings, it implies that the inflammatory
changes observed are secondary only to the viral replication. Using this terminology, one major
differential diagnosis of "inflammation" in a renal allograft – rejection – remains without further
consideration. In my opinion, it is crucial to establish a diagnosis of rejection in the setting of BKN
since patients with BKN are generally treated with lowering the immunosuppression. A prerequisite for
such an approach is the absence of rejection. This is the reason why I preferentially use the term
"BK-Virus nephropathy" to clearly distinguish viral disease from potential concurrent acute allograft
BKN, stage A is typically not associated with significant inflammation
. BKN, stages B and C
can be associated with varying degrees of inflammatory cell infiltrates. Tubular injury results in
back-leak of urine into the interstitial compartment, edema and a mixed inflammatory cell infiltrate
including polymorphonuclear leukocytes . The inflammatory reaction is often rich in plasma cells
including a plasma cell tubulitis likely promoted by tubular expression of cytokines (e.g. IL-1, IL-6,
IL-11, RANTES) and cytokine receptors (IL-4R, IL-13R)
. An inflammatory reaction rich in
lymphocytes and lymphocytic tubulitis should raise the level of suspicion of concurrent rejection.
We diagnose acute rejection in the setting of BKN if we detect the following changes:
All of the
changes are typical for acute rejection and they are not defining features of BKN. The
immunohistochemical detection of C4d and/or MHC-class II appear to be of specific diagnostic value to
support a diagnosis of concurrent acute rejection. C4d is not detected along peritubular capillaries in
"uncomplicated" cases of BKN
. Productive polyomavirus infections seem to be associated with
tubular upregulation of MHC-class I molecules (i.e. HLA-B, HLA-C, HLA-F) but not with the expression of
MHC-class II (i.e. HLA-DR)
. The outlined approach to diagnose acute rejection in the setting
of BKN has largely been adopted by the "Polyomavirus Allograft Nephropathy Consensus Conference" (Basel,
Switzerland, October 2003, ).
transplant endarteritis or fibrinoid arterial wall necrosis,
- transplant glomerulitis,
deposition of the complement degradation product C4d along peritubular capillaries,
lymphocytic inflammation and tubulitis in regions/tubules free of virally induced cytopathic changes (by
LM and IHC), or
- the expression of MHC-class II (HLA-DR) in tubules
The diagnoses of BKN and concurrent acute rejection are not purely academic but rather carry direct
therapeutic consequences. Of note: Productive polyomavirus infections, i.e. persistent cases of BKN,
are not associated with an increased incidence of acute rejection episodes. Thus, BKN does not trigger
Both the detection of "decoy-cells" in the urine and
quantitative PCR analyses on plasma (and urine samples) are useful adjunct tools to assess the risk for
BKN, to indicate the necessity for a graft biopsy and to monitor the response to therapy during
. Figure A illustrates our algorithmic diagnostic and therapeutic
Highlighted below are some key aspects of acute rejection episodes occurring in the
setting of BKN as many clinicians still hesitate to "treat" rejection:
Thus, it seems that attempts are clinically justified to diagnose and treat acute rejection episodes
in the setting of BKN.
- If the therapy of BKN includes low dose immunosuppression, acute
rejection should either be absent or treated adequately.
- Anti rejection therapy follows a "two-step-approach":
- the transient specific
increase of the immunosuppression is subsequently followed by
attempts to treat the BKN (e.g. low dose maintenance immunosuppression,
- Anecdotal reports demonstrate that transient anti rejection treatment (followed
by therapeutic attempts to treat BKN) can result in long-term functional
improvement, resolution of BKN, and even return of kidney function to
- BK-viruses are "slow-actors" (unlike EBV or adenoviruses). Brief increases of
the immunosuppression do not seem to stimulate viral replication. Anecdotal
reports indicate that transient anti-rejection therapy (with bolus steroids or
even anti-lymphocytic preparations) does not result in explosive viral
replication, i.e. plasma viral load levels and the number of decoy cells in the
urine remain unchanged .
- BKN is limited to the allograft; transient anti-rejection therapy has not resulted
in systemic viral spread or mortality (unlike CMV, adenoviruses or EBV).
- Transient anti-rejection treatment may not result in an immediate
improvement of renal function and "therapeutic unresponsiveness" should not
be regarded as evidence for a histologic "misdiagnosis of rejection". If BKN
concurs with acute rejection, then allograft dysfunction is caused to different
induced tubular injury predominates (i.e. BKN stage B), then allograft function
will only improve after BKN has additionally been treated.
- virally induced tubular injury, and
- In general BKN carries an unfavorable long-term prognosis; specific attempts
to treat concurrent acute rejection cannot worsen graft outcome significantly.
The definitive diagnosis of BKN is made in a graft biopsy. The diagnosis should indicate the
pattern/stage of disease (A-C) and comment upon the presence or absence of rejection. Crucial clinical
data required at the time of histologic work-up include information on the activation of polyomaviruses,
i.e. the shedding of decoy cells in the urine and plasma viral load levels. Clinical evidence of
"polyomavirus activation" at time of biopsy should automatically trigger an intensive histologic search
for cytopathic signs (including immunohistochemistry or in-situ hybridization).
In order to treat the
acute cellular tubulo-interstitial rejection episode, the patient under discussion received bolus steroid
therapy in mid November 2004. His baseline immunosuppression was subsequently lowered/changed to
cyclosporine (2x125 mg/day), prednisone (5 mg/day) and leflunomide (40 mg/day). In early December 2004
(less than 4 weeks after the initial diagnosis) renal function had improved and returned to "baseline"
levels (S-Cr 1.7 mg/dl), i.e. the rejection episode had been adequately treated. Not surprisingly
BK-virus load levels remained largely unchanged (urine cytology: 8/decoy cells per 10 HPF; urine PCR:
200.000.000 BK virus copies per ml urine; serum PCR: 8500 BK virus copies per ml serum); long-term
follow-up will be needed to assess the clinical response to leflunomide.
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