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JANUARY 2016

A Man With Chronic Lymphocytic Leukemia and

Declining Kidney Function

ultrasound showed normal-sized kidneys with

CLINICAL PRESENTATION
no hydronephrosis. Urine cytology was reques-
A 56-year-old man with a history of multinodular
ted (Fig 1), and a kidney biopsy was performed
goiter after total thyroidectomy, chest wall mela-
(Figs 2-4).
noma treated with curative resection, and hy-
pertension was given a diagnosis of chronic
lymphocytic leukemia/small lymphocytic lym-
- What are the causes of declining kidney
phoma (CLL/SLL). He received 6 cycles of u-
function in a patient with malignancy?
darabine, cyclophosphamide, and rituximab. The
patient experienced a relapse of CLL 15 months
- What findings are revealed in the urine
after presentation, and a 6-cycle salvage chemo-
sediment examination and kidney biopsy?
immunotherapy protocol with udarabine and
alemtuzumab was planned. After 3 cycles, the - What further tests may aid in the diagnosis?
patient developed aspergillus meningitis, com-
plicated by posterior circulation stroke and
- What are the treatment options for this
lateral medullary syndrome. He was treated with
patient?
voriconazole and had near-complete neurologic
recovery. Chemo-immunotherapy was resumed
after a 3-month interruption, and the remaining 3
cycles were administered. Throughout this period,
kidney function remained stable, with serum
creatinine levels ranging between 0.7 and 1.1 mg/
dL (corresponding to estimated glomerular ltra-
tion rates [GFRs] of 73 to 103 mL/min/1.73 m2 as
calculated by the CKD-EPI [Chronic Kidney Dis-
ease Epidemiology Collaboration] equation).1 Af-
ter he completed therapy, the patients kidney
function progressively deteriorated over a 6-month
period, with serum creatinine level increasing to
2.9 mg/dL (estimated GFR, 23 mL/min/1.73 m2).
He remained normotensive, and urinalysis revealed
nonselective proteinuria with protein excretion of
0.45 g/d without hematuria or leukocyturia. Renal Figure 1. Urine cytology shows a decoy cell (arrow) (original
magnification, 3400). Image courtesy of A. Hadji-Ashrafy.
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xviii Am J Kidney Dis. 2016;67(1):xviii-xxi

Figure 2. Kidney biopsy specimen shows distorted
tubules. Arrows indicate tubular epithelial cells
showing viral cytopathic effect (hematoxylin and
eosin stain; original magnification, 3400).

Figure 3. Immunohistochemical stain of kidney biopsy

specimen for polyomavirus, using an antibody
against SV40 antibody. Arrows show positive nuclei
(original magnification, 3200).

Figure 4. Kidney biopsy specimen shows marked

chronic tubulointerstitial inflammation with promi-
nent lymphocytes suggestive of involvement by
chronic lymphocytic leukemia/small lymphocytic
lymphoma (hematoxylin and eosin stain; original
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magnification, 3200).

Am J Kidney Dis. 2016;67(1):xviii-xxi xix

 QUIZ PAGE
JANUARY 2016
ANSWERS

DISCUSSION - What findings are intranuclear BK polyoma viral in-

- What are the causes of
declining kidney function
in a patient with
malignancy?
GFR loss is common in patients
with malignancy and is often
multifactorial. The causes of
declining kidney function can be
thought of in terms of the mech-
anism underlying the injury, as
well as the kidney compartment
that is injured (Table 1). The
1-year risk for patients with ma-
lignancy developing GFR loss is
w17.5% and correlates with
increased risk for morbidity and
mortality.2
revealed in the urine
sediment examination
and kidney biopsy?
Urine cytology in this patient
revealed decoy cells (Fig 1).
Decoy cells are virally infected
tubular epithelial cells with an
enlarged nucleus containing a sin-
gle large basophilic intranuclear
inclusion. There was also evidence
of viral cytopathic changes and
tubulitis on light microscopy (Fig
2). Staining of the kidney biopsy
specimen with an antibody against
SV40 large T antigen (which
cross-reacts with polyomaviruses)
gave signal in 20% of the tubules;
the staining was consistent with
clusions in tubular cells (Fig 3).
The presence of a monotonous
population of small atypical lym-
phocytes (Fig 4) was suggestive
of lymphomatous involvement of
renal tubulointerstitium.
- What further diagnostic
tests may aid in the
diagnosis?
Polymerase chain reaction quanti-
cation in serum showed more than
10 log copies of BK virus. The
presence of decoy cells, viremia, and
histologic evidence of BK virus in
this patient is indicative of BK virus
nephropathy contributing to wors-
ening kidney function. Native BK

Table 1. Causes of Declining Kidney Function in Malignancy Can Be Classified Both Mechanistically and by the Kidney
Compartment Affected

Kidney Compartment Affected

Intrinsic

Mechanism Prerenal Glomerulus Tubulointerstitium Vascular Intratubular Postrenal

Treatment related NSAIDs, CNIs, Collapsing FSGS AIN TTP/HUS Crystal uropathy
hepatic sinusoidal (pamidronate) (methotrexate)
obstruction
syndrome after
BMT, hypovolemia
from diarrhea,
nausea, vomiting
Cancer related: MIDD, amyloid Infiltration, MIDD Infiltration of Tumor lysis, cast Uretheral/
direct effect renal veins nephropathy bladder
obstruction
Cancer related: Hypercalcemia Membranous GN Hypercalcemia
paraneoplastic
effect
Immunosuppression Sepsis Acute tubular
related necrosis, BK
nephropathy
Abbreviations: AIN, allergic interstitial nephritis; BMT, bone marrow transplantation; CNI, calcineurin inhibitor; FSGS, focal segmental glo-
merulosclerosis; GN, glomerulonephritis; MIDD, monoclonal immunoglobulin deposit disease; NSAID, nonsteroidal anti-inflammatory drug;
TTP/HUS, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome.
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xx Am J Kidney Dis. 2016;67(1):xviii-xxi

virus nephropathy is a rare but
emerging condition in patients
immunocompromised for rea-
sons other than solid-organ or
bone marrow transplantation.3
Clinicians should include BK
virus nephropathy in their differ-
ential diagnosis when assessing
intensely immunosuppressed pa-
tients with malignancy who pre-
sent with GFR loss. When the
diagnosis is not evident, the
clinician should use polymerase
chain reaction amplication of
BK to conrm the diagnosis.
- What are the treatment
options for this patient?
In contrast to the situation with
organ and bone marrow transplant
recipients, reducing immunosup-
pression in patients with GFR loss
and malignancy is not always
possible (although this approach
should be considered when the
patient is diagnosed while under-
going treatment). Instead, treat-
ment should be focused on
antiviral therapy and immuno-
modulation. Unfortunately, con-
vincing evidence for antiviral
therapy is lacking.4 Leunomide
has both immunosuppressive and
antiviral effects. However, its po-
tential adverse hematologic effects
often preclude its use, as in our
case, in which the patient devel-
oped progressive pancytopenia
due to recurrent CLL/SLL. Cido-
fovir has activity against BK virus,
but was excluded because of its
nephrotoxic potential. Brincido-
fovir, a cidofovir analogue without
nephrotoxicity, is emerging as a
new therapy.5 Intravenous im-
munoglobulin (IVIG) may be
effective due to the presence
of BK virus antibodies, whereas
ciprooxacin is known to inhibit
Am J Kidney Dis. 2016;67(1):xviii-xxi
large T antigen helicase activity
in vitro.6 Our patient received an
initial 2-g/kg dose of IVIG split
over 5 weeks. Subsequently, he
received IVIG, 100 mg/kg, weekly
for another 10 weeks. A 1-month
course of ciprooxacin also was
given. The BK viremia did not
respond and his kidney function
continued to deteriorate; he
required renal replacement therapy
4 months later.
FINAL DIAGNOSIS
Native kidney BK nephropathy
and chronic lymphocytic leuke-
mia/small lymphocytic lymphoma
inltration with chronic tubu-
lointerstitial damage resulting in
worsening kidney function.
ACKNOWLEDGEMENTS
The authors thank Associate Profes-
sor Kamal Sud (Nepean Hospital and
University of Sydney Medical School)
for helpful advice and editing the
manuscript; Dr Amir Hadji-Ashrafy
(Department of Pathology, Nepean
Hospital) for providing images of the
decoy cells; and Drs Eddy Fischer
(Nepean Hospital) and Bhadran Bose
(Nepean Hospital and University of
Sydney Medical School) for advice in
preparing the manuscript.
REFERENCES
1. Levey AS, Stevens LA,
Schmid CH, et al. A new equation to
estimate glomerular ltration rate. Ann
Intern Med. 2009;150(9):604-612.
2. Christiansen CF, Johansen MB,
Langeberg WJ, Fryzek JP,
Sorensen HT. Incidence of acute kid-
ney injury in cancer patients: a Danish
population-based cohort study. Eur J
Intern Med. 2011;22(4):399-406.
3. Sharma SG, Nickeleit V,
Herlitz LC, et al. BK polyoma virus
nephropathy in the native kidney.
Nephrol Dial Transplant. 2013;28(3):
620-631.
4. Kidney Disease: Improving
Global Outcomes Transplant Work
Group. KDIGO clinical practice
guideline for the care of kidney
transplant recipients. Am J Trans-
plant. 2009;9(suppl 3):S1-S155.
5. Papanicolaou GA, Lee YJ,
Young JW, et al. Brincidofovir for
polyomavirus-associated nephropa-
thy after allogeneic hematopoietic
stem cell transplantation. Am J Kid-
ney Dis. 2015;65(5):780-784.
6. Portolani M, Pietrosemoli P,
Cermelli C, et al. Suppression of BK
virus replication and cytopathic effect
by inhibitors of prokaryotic DNA
gyrase. Antiviral Res. 1988;9(3):
205-218.
CASE PROVIDED AND AUTHORED BY
James Collett, MBBS,1 Stephen
Fuller, MBBS, PhD,2,3 Chow Heok
PNg, MBBS,4 and Muralikrishna
Gangadharan Komala, MBBS,1
Departments of 1Nephrology and
2
Hematology, Nepean Hospital,
Kingswood; 3University of Sydney,
Sydney; and 4Institute for Clinical
Pathology and Medical Research,
Westmead Hospital, Westmead,
Australia.
Address correspondence to
Muralikrishna Gangadharan
Komala, MBBS, Department of
Nephrology, West Block, Level 3,
Nepean Hospital, Derby Street,
Kingswood, NSW 2747, Australia.
E-mail: mgan5866@uni.sydney.
edu.au
2016 by the National Kidney
Foundation, Inc.
http://dx.doi.org/10.1053/j.ajkd.2015.
09.018
SUPPORT: None.
FINANCIAL DISCLOSURE: The authors
declare that they have no relevant
nancial interests.
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