Clinical Nephrology, Vol. 81 – No.

6/2014 (435-439)

Diffuse parenchymal form of malakoplakia in

Neph
Education
©2014 Dustri-Verlag Dr. K. Feistle
ISSN 0301-0430
DOI 10.5414/CN107506
e-pub: November 29, 2012
renal transplant recipient: a case report
Elizete Keitel1, Karla Lais Pêgas2, Antonio Eduardo do Nascimento Bittar3,
Auri Ferreira dos Santos3, Francisco da Cas Porto3, and Eduardo Cambruzzi4
1Universidade Federal de Ciências da Saúde de Porto Alegre, 2Hospital de Clínicas
de Porto Alegre, Department of Pathology, 3Nephrologist, Santa Casa de Porto
Alegre, 4Universidade Luterana do Brasil (ULBRA), Canos, RS, and
5Universidade Federal do Rio Grande do Sul (UFRGS), Porto Allegre, RS, Brazil

Key words
kidney – transplants
– macrophages – inflam-
mation – inclusion
bodies – malakoplakia
Received
October 12, 2011;
accepted in revised form
September 4, 2012
Correspondence to
Dr. Karla Lais Pêgas
Hospital de Clínicas de
Porto Alegre, Depart-
ment of Pathology, R.
Ramiro Barcellos 2350,
CEP 90035-903, Porto
Alegre, RS, Brazil
lfp.voy@terra.com.br
Abstract. Malakoplakia is an unusual
chronic inflammatory disease related to prior
urinary tract infection. It is characterized by
the presence of macrophages with foamy
cytoplasm exhibiting larger PAS positive
inclusions that stain for calcium and iron.
Malakoplakia affects renal allograft and is
associated with severe morbidity. Herein,
the authors report a new case of renal graft
malakoplakia in a 23-year-old female pa-
tient. The patient received a living-related
donor renal transplantation with a high im-
munological risk. Plasmapheresis and intra-
venous immunoglobulin (i.v. Ig) treatment,
pre- and post-transplant, and induction with
rabbit anti-thymocyte globulins were used
due to presence of donor specific antibodies
and positive B cross match by flow cytom-
etry. The patient had an early urinary tract
infection with a good outcome. On Day 36
post-transplant (PO), the patient returned to
the clinic with fever, graft pain and acute
renal dysfunction leading to hemodialysis.
Escherichia coli (E. coli) were present in the
blood and urine culture. At the time, the renal
biopsy revealed numerous sheets of macro-
phages with foamy, eosinophilic cytoplasm
showing several PAS positive granules and
large inclusions that stained strongly with
hematoxylin, calcium (von Kossa method)
and iron (Prussian blue). The patient was di-
agnosed with malakoplakia related to a kid-
ney transplant. Despite prolonged treatment
with antibiotics, determined by a suscepti-
bility test, the patient did not recover renal
function and remained on dialysis.
Introduction
Malakoplakia is an unusual chronic in-
flammatory disease first described by von
Hansemann [1] and Michaelies and Gutmann
[2]. It most commonly involves the bladder,
but can also occur in the large bowel, pros-
tate, lung, bone, and brain. Malakoplakia
affecting the kidney is associated with sup-
pression of the immune system and prior uri-
nary tract infections, E. coli being the most
common agent. This is a rare cause of renal
failure and few cases have been reported in
transplant patients [3, 4, 5].
Females are affected in a ratio of 3  :  1
over men in the renal form of malakoplakia,
with a mean age of 45 years. Bilateral kidney
involvement is found in 33 – 50% of cases.
It usually affects the cortex and the affected
organ exhibits a lobulated, yellow-brown
nodular lesion that can simulate a malig-
nant neoplasia. The urine contains protein in
variable amounts, leukocytes, and some red
blood cells. Renal allograft parenchyma mal-
akoplakia is not a frequent condition and is
associated with severe morbidity [4, 6, 7, 8].
In the present report, the authors describe
a case of parenchymal malakoplakia in a re-
nal transplant recipient and discuss the clini-
cal and pathological findings of this uncom-
mon lesion and its treatment.
Case report
A 23-year-old female patient, with a pre-
vious diagnosis of chronic glomerulonephri-
tis, began hemodialysis in February 2008.
She received a living-related donor kidney
transplant (recipient HLA: A2,2; B48, 64;
DR 7, 11/donor HLA: A 24, 68; B38, 55;
DR4, 13) in December 2010. Three sessions
of plasmapheresis and IVIg, pre-transplant
and post-transplant (PO), were performed
due to presence of donor specific antibod-
ies (DR 4, 13) and positive B cells that cross
Keitel, Lais Pêgas, do Nascimento Bittar, et al. 436
Figure 1.  Malakoplakia in a renal graft: numerous
macrophages exhibiting larger intracytoplasmatic
inclusions, H & E, × 200.
Figure 2.  Michaelis-Gutmann bodies (arrows),
H & E, × 400.
matched by flow cytometry. The immu-
nosuppression consisted of induction with
rabbit anti-thymocyte globulin, tacrolimus,
sodium mycophenolate, and prednisone. On
Day 7 PO, she presented with renal dysfunc-
tion (serum creatinine: 2.1 mg/dL) and renal
biopsy showed the presence of capillaritis,
glomerulitis, and positive immunostaining
for C4d in ~  30% of the peritubular capil-
laries. Intravenous methylprednisolone 500
mg pulse therapy was added once daily for
3 days. At the same time, the urine culture
revealed E. coli and as a result she received
IV cefuroxime for 14 days. The patient re-
covered renal function and was discharged
on Day 21 PO with a serum creatinine level
of 1.4 mg/dL. On day 36 PO, the patient re-
turned to outpatient clinic after experiencing
fever, chills and abdominal pain for 5 days.
Her urine output was 400 mL/24 h. On ex-
amination, her blood pressure was 100/60
mmHg, pulse rate 110 per minute, respira-
tory rate 20 per minute, temperature 38.0 °C,
and she was mildly dehydrated. The graft was
swollen and painful. Laboratory findings con-
sisted of the following: creatinine: 8.0 mg/dL,
potassium: 6.2 mEq/L, alkaline reserve: 12.6
mEq/L, white blood cells: 12,550/µL, and
lymphocytes: 96/µL. Urinalysis showed: spe-
cific gravity 1.013; pH 7.0; nitrite negative;
protein 3+; white cells 1+, 50 per high power
field (HPF) magnification; and erythrocytes
7 – 9 per HPF. Abdominal ultrasound showed
an enlarged graft without signs of obstruc-
tion. Ciprofloxacin IV was started on the first
day and hemodialysis on the following day.
E. coli was detected in the blood and urine
culture (105 unit forms colony). In response
to the susceptibility test, the antibiotic was
changed to cefuroxime and was given for 28
days.
On the 7th day after hospitalization, a
renal biopsy was performed due to the pa-
tient’s high immunological risk to exclude an
antibody mediated rejection and because she
was not recovering renal function. The bi-
opsy showed no rejection but displayed nu-
merous sheets of macrophages with foamy,
eosinophilic cytoplasm and densely stained
nucleus (Figure 1). Within the cytoplasm of
these cells, numerous PAS positive granules
and large inclusions were found, measur-
ing 4  –  10 microns in diameter and stained
strongly with hematoxylin (Figure 2). These
bodies also stained for calcium (von Kossa
method) (Figure 3) and iron (Prussian blue).
The patient underwent two more renal bi-
opsies during the follow-up. Despite nega-
tive urine culture, malakoplakia increased
to 95% of tissue sample in the final biopsy
(Day 66 PO). The search for decoy cells and
Rhodococcus in urine was negative. During
this period, a positive antigenemia for cy-
tomegalovirus was detected and the patient
was treated with IV ganciclovir. She was
Diffuse parenchymal form of malakoplakia in renal transplant recipient 437
Figure 3.  Michaelis-Gutmann bodies in black with
calcium stain (arrows). Von Kossa Stain × 400.
hospitalized for 49 days, but did not recover
renal function and was discharged on hemo-
dialysis 3 times a week. Nephrectomy of the
graft was not performed during hospitaliza-
tion in order to observe if the patient would
recover renal function. After 3 months, she
was still on dialysis and declined the option
to undergo a nephrectomy.
Discussion
Malakoplakia is an unusual inflammatory
lesion found in many different organs, in par-
ticular the urinary tract. It most likely repre-
sents a defect in the phagocytic activity of
engulfed bacteria by macrophages. The con-
dition is more commonly found in the uri-
nary bladder than renal parenchyma, where it
has a more aggressive course. Malakoplakia
affecting renal transplant tissue is associated
with severe morbidity and is more frequent
in women in the fifth decade of life with a
prior history of bacterial urinary infection;
E. coli is the most common bacteria involved
[9, 10, 11, 12, 13]. The infecting organisms
reach the kidney from the lower urinary tract
by an ascending route, which is frequently
related to vesicoureteral reflux. E. coli is a
gram-negative enteric bacteria with certain
virulence factors, such as K, O and H anti-
gens (capsular polysaccharides), P fimbriae,
and catecholate siderophore receptor (iron),
that stimulates the formation of antibodies
(IgM, IgG, and IgA) in cases of pyelone-
phritis. The exact pathogenetic mechanism
related to the development of malakoplakia
remains unclear. It appears to be associated
with low levels of cyclic GMP and a poor re-
lease of beta-glucuronidase, or an alteration
of the ratio between cyclic GMP and AMP.
Heavy immunosuppression predisposes the
patient to gram-negative bacterial infections
and subsequently to the development of his-
topathological findings related to malakopla-
kia. Augusto et al. described that all cases of
malakoplakia related to kidney were associ-
ated with renal failure and biopsies indicated
acute interstitial nephropathy, the most com-
mon being the parenchymal diffuse pattern
[8, 9, 10, 11, 12, 13].
Approximately half the patients that de-
velop renal malakoplakia are associated with
malignant neoplastic lesions, AIDS, rheuma-
toid arthritis, prolonged therapy with system-
ic corticosteroids, diabetes mellitus, or im-
munosuppressive therapy. Rare cases have
been reported with transplantation. Symp-
toms include fever, chills, and flank pain.
Urinalysis shows proteinuria, pyuria, and he-
maturia. There is no clinical sign specific for
this entity. The hypothesis of malakoplakia
must be considered in renal transplant recipi-
ents presenting acute renal failure associated
with urinary tract infection, since it is associ-
ated with severe morbidity [4, 10, 14, 15].
Computed tomography may show het-
erogeneous renal mass [16]. Our patient did
not undergo a CT scan, but renal ultrasound
showed no nodule or obstruction and it was
compatible with diffuse form of malakoplakia.
On gross examination, renal parenchy-
mal involvement may consist of yellowish or
tan nodules of variable size. The nodules are
clearly visible on the subcapsular surface and
can be seen extending to the papilla. Mala-
koplakia may take a diffuse form, which is
related to renal failure, or a focal form that
can be mistaken for a tumor. In cases affect-
ing the renal pelvis, calices are dilated with
pus in the pelvic cavity and thinning of the
renal parenchyma, which may lead to urinary
obstruction. Perinephric abscesses and bilat-
erality are not uncommon [4, 8, 9, 10, 16].
On microscopic evaluation, the lesion
consists of clusters of moderately large
polygonal cells and/or macrophages with
Keitel, Lais Pêgas, do Nascimento Bittar, et al. 438

Table 1.  Clinical aspects of renal graft malakoplakia.

Study Age/ Bacteria Immunosuppressive Malakoplakia Presenta- Outcome

sex involved regimen treatment tion form
Augusto et al. 56/F E. coli Anti-thymocyte Levofloxacin Diffuse Improvement
[8] globulins/tacrolimus/ in renal
mycophenolate function
mofetil
Puerto et al. 45/F E. coli Not specified Not specified Nodular/ Nephrectomy
[16] focal of the
transplanted
kidney
Osborn et al. 48/F E. coli Prednisone/ Ampicillin Diffuse Hemodialysis
[18] Azathioprine
Pusl et al. 43/F E. coli Mycophenolic acid/ Antibiotic (not Diffuse Improvement
[19] tacrolimus specified) in renal
function
Mullan et al. 42/F E. coli Not specified Not specified Diffuse Nephrectomy
[20] of the
transplanted
kidney
Barker et al. 43/F E. coli Prednisone/ Post-mortem Diffuse Death
[22] Azathioprin diagnosis
Husek et al. 44/F E. coli/ Cyclosporine A/ Piperacillin/ Diffuse Improved after
[23] Citrobacter prednisone pefloxacin 6 months
follow-up

foamy, eosinophilic cytoplasm, and densely
staining nuclei, commonly known as von
Hansemann cells. Within the cytoplasm of
these cells, granules that stain positively
with the PAS method and larger inclusions
measuring 4 – 10 micra in diameter that stain
strongly with hematoxylin can be seen, also
known as Michaelis-Gutmann (MG) bodies.
These bodies stain for calcium (von Kossa
method) and iron (Prussian blue). The PAS-
positive granules in the macrophages cor-
respond to phagolysosomes, which contain
complex membranous whorls and bacteria
in various stages of breakdown [3, 8, 9, 10,
11, 14, 13, 14, 15, 16, 17, 18]. Since a large
number of cases of malakoplakia have been
associated with abnormalities in the immune
system, some consider the hypothesis that a
deficiency in the ability to dispose bacteria
determines the development of large po-
lygonal eosinophilic macrophages. On ultra-
structural evaluation, these intracytoplasmic
inclusions show a crystalline structure with a
central dense core, an intermediate halo, and
a peripheral lamellate ring (lysosomal mem-
brane). Rod-shaped structures resembling
bacteria are often present within phagoly-
sosomes. Other mononuclear and plasma
cells contribute to the reaction causing the
tubules to be severely damaged. Malako-
plakia is also accompanied by an interstitial
fibroblastic and collagenous reaction [3, 8,
9, 10, 11, 17, 18, 19, 20, 21, 22]. Herein,
the authors describe a new case of the dif-
fuse form of malakoplakia in a female renal
transplant recipient related to E. coli urinary
tract infection and over-immunosuppression.
Antibiotics were started 5 days after initial
symptoms. Some case reports that discuss
malakoplakia in renal grafts listed in the lit-
erature are summarized in Table 1.
Since malakoplakia can present as an
expanding, ill-defined mass in the renal
parenchyma, the differential diagnosis in-
cludes xanthogranulomatous pyelonephri-
tis, megalocytic interstitial nephritis, renal
mycobacterium and fungus infection, and
neoplasm [4, 6, 8, 10, 17, 21]. MG bodies
differentiate malakoplakia from xantho-
granulomatous pyelonephritis, which lacks
the characteristically intense PAS staining.
Mycobacterium tuberculosis and fungus in-
fection can be ruled out if the special stains
are negative. Although the best therapy for
malakoplakia is not well defined, some rec-
ommend antibiotics for a prolonged period
of time, such as quinolones and TMP-SMX
[7, 10]. The immunosuppression should be
decreased or even suspended to improve the
bactericidal function of leucocytes and in-
crease the chance for renal function recov-
ery [8, 24].
Diffuse parenchymal form of malakoplakia in renal transplant recipient 439

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