9- Lavazzo2007

european urology 51 (2007) 1534–1541
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Review – Female Urology – Incontinence
Hyaluronic Acid: An Effective Alternative Treatment of
Interstitial Cystitis, Recurrent Urinary Tract Infections, and
Hemorrhagic Cystitis?
Christos Iavazzo a, Stavros Athanasiou a,b, Eleni Pitsouni a, Matthew E. Falagas a,c,*
a
Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece
1st Department of Obstetrics and Gynecology, Athens University School of Medicine, Athens, Greece
c
Department of Medicine, Tufts University School of Medicine, Boston, MA, USA
b
Article info
Abstract
Article history:
Accepted March 9, 2007
Published online ahead of
print on March 20, 2007
Objectives: Hyaluronic acid is a protective barrier of the urothelium. A
damaged glycosaminoglycan layer may increase the possibility of bacterial
adherence and infection. This damage is proposed to be a causative factor in
the development of interstitial cystitis, common urinary tract infections, and
hemorrhagic cystitis due to posthematopoietic stem cell transplantation. The
aim of this article was to review the available data regarding the use of
hyaluronic acid as an alternative treatment of the above-mentioned conditions.
Methods: Articles relevant to our review that were archived by September 2006
were retrieved from PubMed.
Results: Nine relevant studies were identified and evaluated. Hyaluronic acid was
administered intravesically at a dose of 40 mg every week for 4–6 wk; patients
with noted improvement received two additional monthly doses. Short-term
responses of patients with interstitial cystitis, hemorrhagic cystitis, and recurrent urinary tract infections were 30–73% (7 studies), 71% (1 study), and 100%
(1 study), respectively. The treatment was well tolerated except for occasional
development of bacterial cystitis. The cost of each intravesical installation of
hyaluronic acid is 120 UK pounds (excluding the cost of the urinary catheterization).
Conclusions: The available clinical data regarding the effectiveness of hyaluronic
acid as a potential treatment of patients with interstitial cystitis, recurrent
urinary tract infections, and hemorrhagic cystitis are limited. There is need
for randomized controlled trials for further investigation of this important
therapeutics question; these clinical trials should be disease-specific, blinded,
and controlled, and of a sufficient number of patients. Until such studies are
available, intravesical instillation of hyaluronic acid cannot be unquestionably
endorsed for use for the aforementioned diseases.
Keywords:
Hyaluronate
Glycosaminoglycan
replacement treatment
Intravesical administration
Cystitis
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street,
151 23 Marousi, Greece. Tel. +30 694 611 0000; Fax: +30 210 683 9605.
E-mail address: m.falagas@aibs.gr (M.E. Falagas).
0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.03.020
european urology 51 (2007) 1534–1541
1.
Introduction
Hyaluronic acid is a major mucopolysaccharide
found widely in the connective, epithelial, and
neural tissues. It is one of the main components
of the extracellular matrix that contributes significantly to cell proliferation and migration, and may
also be involved in the progression and migration of
some malignant tumors [1]. Hyaluronic acid in the
urothelium constitutes a protective barrier [2,3]. It
exhibits a variety of properties that may contribute
to its prophylactic mechanism [4–10]. Among them
are (1) inhibition of adherence of immune complexes to polymorphonuclear cells; (2) marked
inhibition of leukocyte migration and aggregation,
depending on viscosity; (3) regulation of fibroblast
and endothelial cell proliferation; and (4) enhancement of connective tissue healing. A damaged
glycosaminoglycan layer may lead to direct exposure of epithelial cells to components of urine; for
this reason the possibility of bacterial adherence
and infection increases [8–10]. This damage is
proposed to be a causative factor in the development
of interstitial cystitis [11], common urinary tract
infections (UTIs) [12], and hemorrhagic cystitis due
to posthematopoietic stem cell transplantation [2].
Hyaluronic acid is used in clinical practice in the
treatment of patients with osteoarthritis (by intraarticular injections) [13] or asthma [14]; in certain
ophthalmologic [15] and otologic [16] operations; in
cosmetic regeneration and reconstruction tissue
[17]; and in cystitis [2,3] and vesicoureteral reflux
[18]. The aim of this article is to critically review the
available evidence regarding the use of hyaluronic
acid as an alternative treatment of interstitial
cystitis, recurrent urinary tract infections, and
hemorrhagic cystitis.
2.
1535
microorganisms, and toxic molecules, to the bladder
urothelium [25,26], and urinary hyaluronic acid
levels correlate with interstitial cystitis [27].
There is no specific treatment for interstitial
cystitis because of its uncertain cause and pathogenesis. Tricyclic antidepressants, anti-inflammatory drugs, and a wide range of epithelial-coating
techniques including the use of heparin, sodium
pentosan polysulfate, and hyaluronic acid have
been used [20,22,26,28–31]. Hyaluronic acid is considered a good candidate for glycosaminoglycan
substitution. In addition, heparin and dimethyl
sulfoxide are often used in patients with interstitial
cystitis. These agents’ actions are not quite clear, but
they supposedly act via their anti-inflammatory
effects. Other agents for intravesical treatment are
Bacillus Calmette-Guerin vaccine and botulinum
toxin, and some recent studies have pointed to
resiniferatoxin and RDP58 [32].
3.
Urinary tract infections
UTI is a very common type of bacterial infection,
especially in women. Not every patient with UTI has
symptoms. When symptoms are present, patients
feel urgency, frequency, nocturition with small
voidal volume, bladder or utethra pain during
urination, suprapubic discomfort, and sometimes
fullness in the rectum. Presence of fever, pain in the
back or side below the ribs, nausea, and vomiting
indicates kidney infection [33]. Management of UTIs
involves administration of antibiotics, but a high
percentage of recurrent infections still occur [12].
Contemporary treatment options could also be
estrogen replacement therapy [12], use of cranberry
juice [34] or probiotics [35], as well as glycosaminoglycan substitution by using heparin, sodium
pentosan polysulfate, or hyaluronic acid [12].
Interstitial cystitis
Interstitial cystitis is a chronic disease characterized
by urinary frequency, bladder pain, nocturia, and
urgency. It usually affects women [19]. The prevalence of interstitial cystitis ranges from 10 up to
510 cases per 100,000 population [20,21]. Interstitial
cystitis is frequently a diagnosis of exclusion. Many
etiologic factors [20,22–24] have been suggested for
this condition, including autoimmune response,
mast cell activation, neuropathic changes, occult
infection, toxic substances in the urine, and a
primary defect in the glycosaminoglycan layer of
the bladder mucosa. It has been suggested that a
defect in the glycosaminoglycan layer allows access
of different components of urine, such as ions,
4.
Hemorrhagic cystitis
Hemorrhagic cystitis is a relatively common (incidence: 7–68%) and potentially severe complication
of high-dose chemoradiotherapy, especially in conjunction with hematopoietic stem cell transplantation. There is no established effective treatment for
this type of cystitis [2].
5.
Literature search
Using the online PubMed database, we searched for
articles relevant to our study that were archived by
Year
No. of
patients
Miodosky
et al [2]
2006
7
Daha
et al [19]*
2005
48
32/48 patients with
a Cmax of <350 cc (group 1)
16/48 patients with
a Cmax of >350 cc (group 2)
Gupta
et al [22]*
2005
38
Kallestrup
et al [20]
2005
20
Age (yr)
Mean: 54
(range: 22–82)
34–80
Treatment of
Treatment
scheme
Results
Hemorrhagic cystitis
after HSCT
4 weekly doses plus
monthly doses
5/7 complete response at a
median of 12 d (range: 7–23)
1/7 partial response
1/7 no response (death from
septic shock)
No local or systemic side effects
Interstitial cystitis
(but a bladder capacity
of >350 cc on a 0.9% NaCl
cystometry was accepted)
10 weekly doses
41/48 improvement
27/32 (84%) in group 1
Interstitial cystitis
6 weekly doses and
choice of continuing
monthly in responders
20/36 improvement (55%)
after 6 doses
(74% of PST-positive
patients and 23%
of PST-negative patients)
3 patients referred pain
3 patients developed UTI
Current cost: UK 120 pounds,
excluding nursing and
day-surgical unit costs
Inconvenience of weekly visits
Loss of working time and
earnings
Interstitial cystitis
4 weekly doses plus
2 monthly doses plus
choice of continuing
monthly in responders
40% decrease in nocturia
30% decrease in pain
Decrease in analgesic use
13/20 responders (65%)
6/20 lack of response
1/20 withdrawn due to
cystectomy
Well tolerated by all patients
5/20 bacterial cystitis
due to repeated catheterisation
No correlation between
efficacy and
time of retained solution
in the bladder
After 3 yr: 4/13 complete
responders, 7/13 partial
responders
2/13 other diseases during follow-up
Follow-up
6 mo
(3–16 mo)
14/16 (87%) in group 2
3 yr
european urology 51 (2007) 1534–1541
Author
1536
Table 1 – The role of intravesical use of hyaluronic acid in cystitis
2004
40
Mean: 35
(range: 18–45)
Recurrent UTIs
4 weekly doses
plus 4 monthly doses
40/40: recurrence free during 5 mo
28/40 (70%): recurrence free during follow-up
Median time of recurrence 498 d
(compared with 96 d before treatment)
Excellent tolerability
9/40 mild bladder irritation
40/40 compliance
12.4 mo
Leppilahti
et al [38]
2002
11
Mean: 64.5
(range: 51–76)
Interstitial cystitis
4 weekly doses
8/11 responders
3/8 long-term responders
5/8 short-term responders
Responders: 75% decrease in pain
Long-term responders: 40% decrease
in frequency
Short-term responders:
26% % decrease in frequency
1 yr
Nordling
et al [26]
2001
20
Interstitial cystitis
4 weekly doses
plus monthly
doses for 2 mo
1/20
7/19
6/19
4/19
2/19
3 yr
Morales
et al [3]
1997
25
Interstitial cystitis
4 weekly doses
plus monthly doses
for 1 yr responders
16% complete response by week 4
25% complete response by week 24
56% response (complete or partial) for week 4
71% response (complete or partial) by week 12
71% response (complete or partial) till week 20
Decrease beyond rate 24 weeks
No significant toxicity
1/25 withdrew because of exacerbation
of bladder irritability
6 mo
Porru
et al [39]*
1997
10
Interstitial cystitis
6 weekly doses
plus monthly doses
30% response in 6 weeks
30% response in 24 weeks
No significant local or general side effects
Well tolerated
6 mo
withdrawn due to cystectomy
responders
nonresponders
recovered during treatment
stopped before follow-up
european urology 51 (2007) 1534–1541
Constantinides
et al [12]
HSCT = hematopoietic stem cell transplant; Cmax = maximum plasma concentration; PST = potassium sensitivity test; UK = United Kingdom; UTI = urinary tract infection.
These three studies were randomised controlled trials. The studies by Gupta et al and Porru et al were double-blinded, placebo-controlled trials. Porru et al did not report the method used for
double-blinding, while Gupta et al reported that the pharmacy supplied the medications in bottles labeled A and B to ensure double-blinding.
*
1537
1538
european urology 51 (2007) 1534–1541
September 2006. The key words we used in our
literature searches were hyaluronic acid, hyaluronate, cystitis.
6.
Study selection and evaluation
The focus of our study was in articles that described
the role of hyaluronic acid in the prevention or
treatment of different types of cystitis. Only English
language studies were included in this review. We
identified a total of 27 potentially relevant articles.
From these, 15 were excluded because they did not
focus on the topic of our study. In addition, 3 articles
were excluded because they were animal studies. As
a result 9 studies remained that met the inclusion
criteria of our review. Relevant data were extracted
from each study and tabulated. The information
retrieved included the number of patients, the
route of hyaluronic acid administration, the results
(positive or negative), and the follow-up of each
study.
7.
is from 30% [39] up to 73% [38], and the long-term
(3 yr) response of such patients could reach 55%
[20]. Miodosky et al [1] reported that the total
response to the treatment in patients with hemorrhagic cystitis is 71%. Constantinides et al [12]
found that, in patients with recurrent UTIs, intravesical treatment with hyaluronic acid was associated with absence of recurrence in 100% and
70% of patients during 5-mo and 1-yr follow-up,
respectively.
8.
Adverse events
The use of hyaluronic acid is usually well tolerated
[2,12,19,20,22,26,36–39]; for this reason high compliance with the treatment was achieved in the
reviewed studies and is also expected in clinical
practice. No serious local or systemic adverse events
were mentioned in the reviewed studies, except
mild bladder irritation. A reported adverse event
was bacterial cystitis that was most likely related to
the repeated urinary catheterization rather than the
therapeutic agent itself.
Critical review of the available evidence
From our literature search we found seven studies
[19,20,22,26,36–39] that investigated the role of
hyaluronic acid in the treatment of patients with
interstitial cystitis (total number of patients: 172),
one study [12] regarding the treatment of patients
with recurrent UTIs (total number of patients: 40),
and one study [2] regarding the treatment of
patients with hemorrhagic cystitis (total number
of patients: 7). In Table 1 we present the data
extracted from the relevant reviewed studies.
Patients received four to six weekly intravesical
installations of hyaluronic acid at a dose of 40 mg in
a volume of 50 ml of phosphate-buffered saline.
Responders then received monthly doses. The
intravesical installation was performed with the
use of a catheter, under sterile conditions, after
removal of residual urine. The patients retained the
intravesical hyaluronic acid for a minimum time of
30 min [2,12,19,20,22,26,36–39]. Kallestrup et al [20]
found no correlation between the retention time in
the bladder (range: 28–155 min) and the effectiveness of hyaluronic acid. Gupta et al [21,37] and Daha
et al [19] proposed the use of a positive potassium
sensitivity test before the use of hyaluronic acid to
identify patients with predominant epithelial dysfunction, who are thought to be better responders to
this treatment.
The available data suggest that the total shortterm response of patients with interstitial cystitis
9.
Cost
The cost of each intravesical installation of hyaluronic acid is 120 UK pounds. This figure does not
include the cost of the urinary catheterization, the
cost of the services of the health care personnel, and
the loss of working time and earnings due to the
need for intravesical administration of the drug [22].
For these reasons, we believe that cost-effectiveness
analyses regarding the use of hyaluronic acid in
patients with the examined diseases should be
performed.
10.
Limitations in the interpretation of the
available evidence
The major issue in interpreting the available
evidence regarding the effectiveness and safety of
hyaluronic acid for the examined diseases is that
there are only limited relevant published data. Thus,
one cannot make definitive statements on the
reviewed topics. In addition, an important limitation
of the evaluated studies is the fact that only three of
the nine reviewed studies were randomized controlled trials. It should be mentioned that, in two of
these three trials, hyaluronic acid was compared
with placebo, while in one of these three trials
women were stratified by bladder capacity or
european urology 51 (2007) 1534–1541
potassium chloride test, and pre- and protreatment
analyses were done. While this methodology has
several advantages, we should emphasize that this
new therapeutic modality was not compared with
other commonly used therapeutic options in
patients with the examined diseases. In addition,
the statistical significance and the cut-off of significance were reported in only six of the reviewed
articles, the number of dropouts from the study and
the reason that led participants to dropout were
reported in three articles, and specific information
regarding adverse events of intravesical treatment
with hyaluronic acid in were reported in six articles.
Finally, it should be emphasized that intravesical
hyaluronic acid is not an approved treatment for the
examined indications in the United States and
United Kingdom at the time of writing of this article
(November 2006).
11.
Conclusions
There is a scarcity of data regarding the mode of
action of hyaluronic acid as well as its effectiveness
for the examined diseases in this article. The limited
available evidence from the reviewed studies suggests that hyaluronic acid may be considered for
further studies, including randomized controlled
trials with adequate power. These clinical trials
should be disease-specific, blinded, and controlled,
and include a sufficient number of patients to
answer the important relevant study questions. Until
such studies are available, the effectiveness of
intravesical instillation of hyaluronic acid as a
potential alternative treatment of interstitial cystitis,
recurrent UTIs, and hemorrhagic cystitis remains
unknown.
Conflicts of interest
There are no financial or other relationships that
might lead to a conflict of interest.
Funding: None.
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european urology 51 (2007) 1534–1541
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Editorial Comment on: Hyaluronic Acid: An
Effective Alternative Treatment of Interstitial
Cystitis, Recurrent Urinary Tract Infections,
and Hemorrhagic Cystitis?
Lindsay E. Nicolle
Departments of Internal Medicine and Medical
Microbiology, University of Manitoba, Winnipeg,
MB R3A 1R9, Canada
lnicolle@hsc.mb.ca
In this issue, Iavazzo et al review studies
evaluating the use of intravesical instillation of
hyaluronic acid, a glucosaminoglycan replacement
therapy, for management of interstitial cystitis,
recurrent urinary tract infection, or hemorrhagic
cystitis [1]. The hyaluronic acid solution is instilled
directly into the bladder, and repeated instillations
are necessary. An effective treatment for any of
these clinical entities could be enthusiastically
embraced. However, these syndromes are characterized by remission and relapse and the short-term
course for any given patient cannot be predicted.
Unfortunately, as the review concludes, available studies are limited in number and quality. The
authors identified only nine studies: one involving
[32] Toft BR, Nordling J. Recent developments of intravesical
therapy of painful bladder syndrome/interstitial cystitis:
a review. Curr Opin Urol 2006;16:268–72.
[33] Falagas ME, Gorbach SL. Urinary tract infections:
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juice; potential use for the treatment of urinary tract
infections. J Urol 1984;131:1013–6.
[35] Falagas ME, Betsi GI, Tokas T, et al. Probiotics for prevention of recurrent urinary tract infections in women: a
review of the evidence from microbiological and clinical
studies. Drugs 2006;66:1253–61.
[36] Riedl CR, Daha LK, Pfluger H, et al. Intravesical hyaluronic
acid for the treatment of interstitial cystitis. J Urol
2003;169(Suppl A):265.
[37] Gupta SK. Re: Daha LK, Riedl CR, Lazar D, Hohlbrugger G,
Pflüger H. Do cystometric findings predict the results of
intravesical hyaluronic acid in women with interstitial
cystitis? Eur Urol 2005;47:393–7. Eur Urol 2005;48:534.
[38] Leppilahti M, Hellstrom P, Tammela TL. Effect of diagnostic hydrodistension and four intravesical hyaluronic
acid instillations on bladder ICAM-1 intensity and
association of ICAM-1 intensity with clinical response
in patients with interstitial cystitis. Urology 2002;60:
46–51.
[39] Porru D, Tinelli C, Gerardini M, et al. Results of treatment
of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int 1997;59:26–9.
40 patients with urinary infection, one examining
5 patients with hemorrhagic cystitis, and seven
studies on interstitial cystitis. They identify flaws,
including statistical methodology and reporting of
adverse effects. Only three studies were randomized trials, one of which used two different
regimens of hyaluronic acid. Although the authors
suggest two studies were double-blind and placebo-controlled, both of these, on inspection, are
uncontrolled ‘‘before and after’’ studies [2,3]. Thus,
the knowledge base is insufficient to support any
conclusion about the role of hyaluronic acid
bladder instillations.
Placebo-controlled trials are essential to assess
the efficacy of any therapy for chronic diseases
without an accepted optimal treatment and with an
unpredictable clinical course. For interstitial cystitis
and recurrent urinary tract infection, prospective,
randomized, placebo-controlled trials of potential
therapies have repeatedly been published; such
studies are certainly feasible. It is unfortunate
that any potentially effective therapy has not
been evaluated in appropriate clinical trials and
unfair to promote interventions to patients who
suffer from distressing illnesses before efficacy is
european urology 51 (2007) 1534–1541
documented. We await, with interest, publication of
well-conducted, randomized, placebo-controlled
trials evaluating the use of intravesical hyaluronic
acid for any urologic syndrome.
References
[1] Iavazzo C, Athanasiou S, Pitsouni E, Falagas ME. Hyaluronic acid: an effective alternative treatment of inter-
1541
stitial cystitis, recurrent urinary tract infections, and
hemorrhagic cystitis? Eur Urol 2007;51:1534–41.
[2] Gupta SK, Pidcock L, Parr NJ. The potassium sensitivity
test: a predictor of treatment response in interstitial
cystitis. BJU Int 2005;96:1063–6.
[3] Porra D, Tinelli C, Gerardini M, et al. Results of treatment
of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int 1997;59:26–9.
DOI: 10.1016/j.eururo.2007.03.021
DOI of original article: 10.1016/j.eururo.2007.03.020