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Incidence of Deflux
calcification
masquerading as distal ureteric calculi
on ultrasound
Francisca Yankovic
a
, Robert Swartz
d
, Peter Cuckow
a
,
Melanie Hiorns
b
, Stephen D. Marks
c
, Abraham Cherian
a
,
Imran Mushtaq
a
, Patrick Duffy
a
, Naima Smeulders
a,
*
a
Department of Paediatric Urology, Great Ormond Street Hospital NHS Foundation Trust,
Great Ormond Street, London WC1N 3JH, UK
b
Department of Paediatric Radiology, Great Ormond Street Hospital NHS Foundation Trust,
Great Ormond Street, London WC1N 3JH, UK
c
Department of Paediatric Nephrology, Great Ormond Street Hospital NHS Foundation Trust,
Great Ormond Street, London WC1N 3JH, UK
d
Department of Urology, Orebro University Hospital, Orebro, Sweden
Received 10 September 2012; accepted 31 October 2012
Available online 24 November 2012
KEYWORDS
Dextranomer-
hyaluronic acid;
Deflux
;
Calcification;
Ureteric calculus;
Ultrasound
Abstract Objective: Dextranomer-hyaluronic acid (Deflux
), the most widely used compound
in the endoscopic treatment of vesico-ureteric reflux (VUR) today, is believed to provoke only
minimal inflammation. Reports of calcification of Deflux
are increasing. We ascertain the inci-
dence of Deflux
calcification appearing as distal ureteric calculi on ultrasound.
Methods: Three cases (2 external patients) of ureteroscopy for calcified submucosal Deflux
prompted a retrospective review of the notes and imaging of all children treated with Deflux
for VUR between December 2000 and January 2011 at Great Ormond Street Hospital.
Results: 232 children (M:FZ5:3) received Deflux
for VUR at median age 2 years (range 2
monthse12 years). Follow-up annual ultrasound, performed in all, identified calcification in
2. The interval between Deflux
injection and presentation of its calcification was 4 years.
104 of the 232 children had been followed up for 4e10 years. Considering the observed lag-
period, after 4 years the incidence of calcification of Deflux
on ultrasound was 2% (2/104).
* Corresponding author. Tel.: þ44 20 74059200; fax: þ44 20 78138260.
E-mail addresses: Francisca.yankovic@gosh.nhs.uk (F. Yankovic), Robert.swatrz@orebroll.se (R. Swartz), Peter.cuckow@gosh.nhs.uk
(P. Cuckow), Melanie.hiorns@gosh.nhs.uk (M. Hiorns), Stephen.marks@gosh.nhs.uk (S.D. Marks), Abraham.cherian@gosh.nhs.uk
(A. Cherian), Imran.mushtaq@gosh.nhs.uk (I. Mushtaq), pgduffy@doctors.org.uk (P. Duffy), naima.smeulders@gosh.nhs.uk
(N. Smeulders).
1477-5131/$36 ª2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jpurol.2012.10.025
Journal of Pediatric Urology (2013) 9, 820e824
Author's personal copy
Conclusions: Patients should be warned that calcification of Deflux
can occur. Misinterpreta-
tion as ureteric stones is common and may lead to unnecessary ureteroscopy. In this series, the
incidence of calcification of Deflux
on ultrasound after 4 years was 2%.
ª2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction
Three cases of ureteroscopy for presumed distal ureteric
calculi prompted a review of the notes and imaging of all
children treated with Deflux
for vesico-ureteric reflux
(VUR). Injection of Deflux
for VUR was believed to provoke
only minimal inflammation [1]. More recently, calcification
in addition to fibrosis and eosinophilic infiltration has been
observed on histology [2]. Since then, clinical case reports
of calcified Deflux
masquerading as ureteric stones have
begun to emerge [3e8]. We ascertained the incidence of
Deflux
“stones” on ultrasound.
Materials and methods
The notes and imaging of all children treated with Deflux
for
VUR between December 2000 and November 2011 were
reviewed. The definition of Deflux
calcification required
detection of a hyper-echogenic focus with post-enhancement
shadowing on ultrasound reported as a calculus by a Consul-
tant Paediatric Radiologist.
Positive cases prompted further assessment clinically,
radiologically, metabolically and in one case by uretero-
scopy. We report two further cases, one referred for
ureteric calculi following Deflux
, and one case managed
by a collaborative institution. The density of calcified
lesions on computerised tomography was expressed as the
average density of the region of interest.
Results
During the study period, 232 children (144 boys, 88 girls)
received endoscopic submucosal injection of Deflux
for
VUR at a median age of 2 years (range 2 monthse12 years).
A second injection was performed in 16 children at median
1 year later (range 6 monthse7 years). Clinical and annual
ultrasound follow-up was available for all, for 1e10 years
after injection of Deflux
. A minimum 4 years follow-up
was available for just under half the patients (104/232).
In two patients, hyper-echogenic foci with acoustic shad-
owing, reported as distal ureteric calculi, without change in
hydro-ureteronephrosis were observed on ultrasound.
Case 1
In an asymptomatic 4½-year-old boy with bilateral VUR
(grade 5) and chronic kidney disease (CKD stage 3), ultra-
sound 4 years after Deflux
reportedly showed 2 distal
ureteric calculi (13 mm and 5 mm) without significant
hydro-ureteronephrosis, not seen on the previous annual
ultrasound scans (Fig. 1). Calcification of Deflux
was
questioned, but CT demonstrated 2 stones with average
densities of 850 and 600 Hounsfield Units (HU), respectively
(Fig. 2). However, ureterorenoscopy (4.5/6.5 Fr semi-rigid
Wolf ureteroscope) showed the ureter and pelvi-calyceal
system to be stone free. Instead, two golden-yellow hard
protuberances could be seen deep to the urothelium within
the ureteric orifice. Serum and urinary metabolic stone
screen was normal, including urine calcium:creatinine ratio
(0.29 mmol/mmol).
Case 2
An asymptomatic 15-year-old boy, with antenatal bilateral
hydro-ureteronephrosis and megacystis, who had a bilateral
Cohen ureteric re-implant at the age of 17 months, fol-
lowed by formation of a Mitrofanoff channel for intermit-
tent catheterisation at 3 years of age, was found to have
a 9 mm ureteric calcified focus 4 years after endoscopic
injection of 1 ml of Deflux
to the re-implant tunnel. Serum
and urinary metabolic stone screen was normal, including
urine calcium:creatinine ratio (0.05 mmol/mmol). Cystos-
copy has not been performed. He is currently being worked
up for a renal transplant (CKD stage 5).
We report two further cases, one referred to our insti-
tution after negative ureteroscopy for ureteric calculi, and
one case managed by a collaborative unit.
Case 3 (external referral)
Distal-ureteric echogenic foci with acoustic shadowing were
found on ultrasound performed for abdominal pain and
intermittent vomiting in a 3½-year-old girl with chromosome
4p deletion, 2½ years after Deflux
for VUR. Ureteroscopy
was negative for ureteric stones and a JJ stent was inserted.
CT scan (Fig. 3) showed a 6 mm lower pole calculus (average
density 720 HU) and multiple bilateral radiodense opacities
(upto 10 mm) of lower attenuation than the renal calculus in
the distal ureters posterior to the vesico-ureteric junctions,
attributed to calcified Deflux
(average densities right 540
and left 590 HU). Subsequently, an upper gastro-intestinal
contrast study excluded intestinal malrotation but
confirmed marked gastro-oesophageal reflux as the aetiology
for her symptoms.
Case 4 (collaborative unit)
Left hydro-ureteronephrosis above 2 distal ureteric calcifi-
cations (8 mm and 5 mm) was observed on an abdominal CT
for trauma in a 7-year-old boy after a low-impact fall
(Fig. 1). He had received Deflux
for left VUR (grade 5) 4
years earlier. Following initial JJ stenting, ureteroscopy
found the ureter to be stone free. An intra-operative
retrograde study showed faint extra-luminal calcification.
The interval between Deflux
injection and presentation
of its calcification was 2½, 4, 4, and 4 years. Of the 232
children in the series, 104 had been followed up for
Deflux
calcification on ultrasound 821
Author's personal copy
a minimum of 4 years. The incidence of calcification of
Deflux
on ultrasound was calculated at 2% (2/104) after 4
years.
Discussion
The misinterpretation of calcified dextranomer-hyaluronic
acid (Deflux
) as ureteric stones was first reported in 2008
[3]. A total of 7 cases have been published so far [3e8]. This
study provides the first indication of the incidence of
Deflux
“stones” on routine ultrasound. Two of 232 children
treated with Deflux
for VUR were reported by Consultant
Paediatric Radiologists to have distal ureteric stones on
ultrasound (Cases 1 & 2). These were not seen on annual
scans during the prior 4 years after Deflux
injection.
Considering this lag-period, the incidence of dextranomer-
hyaluronic acid calcification based on a minimum follow-up
of 4 years is 2% (2/104) on ultrasound.
Minimally invasive treatment for vesico-ureteric reflux
(VUR) by endoscopic injection of dextranomer-hyaluronic
acid is well established. Since its introduction in 1998,
world-wide over 50,000 children have received Deflux
[9].
A granulomatous inflammatory reaction is induced at the
injection site with in-growth of fibroblasts and new collagen
deposition [1]. More recently, calcification has been
observed on histology in two thirds of distal ureters, ob-
tained from patients undergoing ureteric re-implantation
after previous endoscopic treatment with dextranomer-
hyaluronic acid [2,10]. Although these histological findings
may have little, if any, significance for the efficacy of
Deflux
in the treatment of VUR, they confirm that calci-
fication of dextranomer-hyaluronic acid occurs.
The reason for the calcification of Deflux
is unclear.
Different theories have been proposed including localised
hypercalcaemia, the precipitation of calcium salts from the
dextranomer-hyaluronic acid formulation, microbial infec-
tion or as a result of the inflammatory reaction [2]. Both our
cases are actively managed for chronic kidney disease
associated with VUR disease, including 1-alfacacidol
therapy. They have been free of urinary tract infection
since the injection of Deflux
and have normal levels of
plasma and urinary calcium.
Although dextranomer-hyaluronic acid implants can be
visualised as iso-echoic blebs in a significant proportion of
patients on ultrasound [12], in both our cases the implants
could not be differentiated from the neighbouring soft tissues
on annual ultrasound scans in the 4 years prior to their
Figure 1 Ultrasound images of Case 1 and Case 4. White arrows indicate the hyper-echogenic foci with post-enhancement
shadowing at the vesico-ureteric junction, indistiguishable in appearance from distal ureteric calculi. Note the ureteric dilata-
tion proximal to the focus in Case 4, which was pre-existing and not indicative of obstructive stones.
Figure 2 Coronal CT image (A) and intra-operative radiograph (B) of Case 1. One of the 2 distal ureteric “stones” demonstrated
on CT can be observed superomedial to the right acetabulum in A. Their average densities were 850 and 600 HU, similar to bone. At
ureterorenoscopy, 2 golden-yellow hard protuberances could be seen deep to the urothelium within the ureteric orifice. Two faint
densities can just be seen alongside the guidewire and immediately above the ureteroscope (black arrows) on an intra-operative
radiograph (B).
822 F. Yankovic et al.
Author's personal copy
appearance as hyper-echogenic foci with post-enhancement
shadowing. While other implants, e.g. polytef (Teflon,
DuPont), appear hyper-echogenic with acoustic shadowing on
ultrasound immediately after injection with echogenicity
static over time, the calcification of Deflux
appears to be
progressive and may appear years after injection [13].
On computerised tomography (CT), Cervinka et al.
observed the density of all Deflux
implants to increase
with time after surgery [14]. In their series of 893 Deflux
patients, 17 underwent CT imaging 2 months to 4 years
after infection of Deflux
. Three children had repeated
CT scans over a 17-month period, documenting median
density increases from 193 to 387 Hounsfield Units (HU).
The density of a vial of dextranomer-hyaluronic acid in
comparison is just 24 HU [13].
As in Cervinka et al.’s experience, the tomography scout
films of the patients presented here (Case 1 and two external
patients eCases 3 & 4) did not demonstrate the calcification.
Only a faint extra-luminal density was observed in Case 4
during the intra-operative retrograde study and a single
poorly defined density in the right half of the pelvis was
visible on a plain film prior to ureterorenoscopy in Case 1. In
this latter case, the average densities of the Deflux
implants on CT were 850 and 600 HU, much greater than any
of the implants in Cervinka et al.’s series [14]. They
compared children with calcified Deflux
to children with
ureteric stones and observed that even the most high-density
Deflux
implants were consistently less than 400 HU. In
contrast, ureteric calculi radio-opaque on plain film had
a median density of 818 HU (range 364e1335 HU), while the
median density of radio-lucent stones was 247 HU
(180e307 HU) [14]. A CT scan was also performed, after
negative ureterorenoscopy, for Case 3. This demonstrated
a 6 mm lower pole calculus (average density 720 HU) in
addition to multiple bilateral distal ureteric radiodense
opacities (upto 10 mm in diameter), attributed to calcified
Deflux
. These had lower attenuation than the renal calculus
(average densities right 540 and left 590 HU). Of note,
three of the four patients appeared to have two or more
calcifications in the distal ureter. Whether this reflects
multiple small injections of Deflux
or its subsequent
fragmentation is unknown.
Considering the apparent progressive nature of calcifica-
tion of Deflux
and the growing numbers of children with
Deflux
implants reaching adulthood, it is likely that adult as
well as paediatric urologists will increasingly have to face
the diagnostic dilemma posed by calcified dextranomer-
hyaluronic acid.
Two of the four patients (Cases 1 & 2) described were
asymptomatic and the distal ureteric calculi observed on
ultrasound examination were an incidental finding.
Although a proportion of children with urolithiasis are
asymptomatic, at least half will present with colicky
abdominal pain and/or haematuria [11]. In 5 of the 7
previously reported cases, non-specific abdominal pain
prompted imaging which included renal ultrasound and CT
scan. However, abdominal pain is a common symptom in
childhood and can have many causes. Indeed, in a third
child (Case 3), referred after a negative ureteroscopy for
distal ureteric stones at her local unit, the aetiology of the
pain was gastro-oesophageal reflux. It is noteworthy, that
neither these cases nor those previously published suffered
haematuria or urinary tract infection.
To arrive at the correct diagnosis, the key points to
obtain for a calcified lesion in the distal ureter are the
background of previous endoscopic VUR treatment and
a detailed clinical assessment including the characteristics
of any pain, presence of haematuria and precipitating
factors for stone formation. The ultrasound appearances
may be indistinguishable from true ureteric stones and the
lack of distal ureteric calcification on ultrasound in prior
years is immaterial. However, stable or improved hydro-
ureteronephrosis makes a diagnosis of calcified Deflux
more probable. A CT scan with attenuation value may help
to differentiate calcifying Deflux
from denser urinary tract
stones, where these co-exist. A high index of suspicion is
Figure 3 CT reconstruction of Case 3. Where calcified Deflux
co-exists with urolithiasis, a CT with attenuation values may help
to distinguish calcified Deflux
from stones. Here the average density of the single right lower pole renal calculus (dotted white
arrow) was 720 HU. The average densities of the multiple Deflux
beads (solid white arrows) were 540 HU on the right and 590 HU
on the left.
Deflux
calcification on ultrasound 823
Author's personal copy
required if unnecessary interventions are to be avoided. Of
the 11 patients reported in the literature [3e8], including
the four children in this series, seven have undergone
endoscopic assessment. While ureterorenoscopic evalua-
tion is a minimal invasive technique, general anaesthesia is
required and major complications can occur.
Conclusions
Patients should be warned that calcification of Deflux
can
occur. The incidence of calcified Deflux
after long-term
follow-up with ultrasound in asymptomatic patients was
2% at a minimum of 4 years after injection. We stress the
importance of recognising this problem, as misinterpreta-
tion as ureteric stones is common and may lead to unnec-
essary invasive investigations.
Conflict of interest statement
None.
Funding source
None.
Ethical approval
Institutional approval obtained.
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