Nephrol Dial Transplant (2003) 18: 2482-2485
© 2003 European Renal Association-European Dialysis and Transplant Association
Editorial Comment
Icodextrin-associated peritonitis: what conclusions thus far?
Eric Goffin1,
Jean-Pierre Cosyns2,
Françoise Pirson3 and
Olivier Devuyst1
1Division of Nephrology, 2Division of Pathology and 3Division of Pneumology, Université Catholique de Louvain Medical School, Brussels, Belgium
Correspondence and offprint requests to: Eric Goffin, MD, Division of Nephrology, Université Catholique de Louvain Medical School, 10 Avenue Hippocrate, B-1200 Brussels, Belgium. Email: goffin{at}nefr.ucl.ac.be
Keywords: allergy; hypersensitivity; icodextrin; peritonitis; peritoneal dialysis; peptidoglycan
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Introduction
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Icodextrin 7.5% (Extraneal; Baxter Healthcare, McGaw Park, IL,
USA) is an iso-osmolar formulation of maltodextrin glucose polymer
derived from starch that is increasingly used to enhance ultrafiltration
during long dwells in continuous ambulatory peritoneal dialysis
(CAPD) and automated peritoneal dialysis (APD) patients [
1–
3].
Since its introduction in the UK in 1994, icodextrin has been
used in more than 23 000 patients in many parts of the world
[
4]. Except for rare cutaneous hypersensitivity reactions [
5,
6],
icodextrin is generally safe and well tolerated. Within the
last 3 years, however, several reports of sterile chemical peritonitis
have been attributed to icodextrin prescription [
7–
19].
In this comment, we will briefly review the clinical and physiopathological
aspects of this syndrome.
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Clinical presentation of icodextrin-associated peritonitis
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Typically, peritoneal dialysis (PD) patients with icodextrin-associated
sterile peritonitis are admitted with abdominal discomfort and
cloudy dialysate effluents. No associated rash, fever or other
hypersensitivity manifestations are present. Many patients have
noticed that dialysate effluents were mainly cloudy under icodextrin
and that they progressively cleared under glucose-based solutions
[
14,
19]. Cell count in the effluent varies from 100 to 3500
white blood cells/µl [
14]. It shows a predominance of
mononuclear cells (macrophages and/or monocytes) [
14], although
neutrophils and lymphocytes have also been identified [
12].
An excess of eosinophils has also been reported in some patients
[
14,
17]. Most importantly, all dialysate cultures remain sterile,
even in enriched media [
12–
15,
19]. Usually, icodextrin
has to be discontinued to clear the dialysate effluents, although
we have observed that symptoms may progressively subside in
a few cases despite maintenance of icodextrin prescription [
14].
In addition, re-challenge often results in re-appearance of
cloudy dialysates within a few days [
7,
8,
12–
14].
The delay between initiation of icodextrin and the first symptoms ranges from a few hours, i.e. the first exchange [7,8], to several months [9,11,14]. Finally, the symptoms may also occur in the resolution phase of an infectious peritonitis [10–11,16].
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What is the prevalence of the syndrome?
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Williams and Foggensteiner [
12] initially reported the occurrence
of these symptoms in 20% (3/15) of their patients exposed to
single exchanges of icodextrin in an early-start dialysis programme.
Subsequently, the same group extended their series with an incidence
of 46% (12/26 patients) [
15]. We found nine such cases in our
icodextrin-using population of 104 patients (8.7%) [
14], whereas
MacGinley
et al. [
13] reported a prevalence of 4.3% (6/141 patients).
It is likely that this prevalence is underestimated because
of the absence of clinical symptoms and/or of detection of cloudy
dialysates in some patients. The fact that, on APD, the presence
of cloudy dialysates is less easily detected probably explains
the clustering of this entity in CAPD patients.
|
What are the consequences?
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At admission, the vast majority of patients has been initially
diagnosed as having an infectious peritonitis and was given
empirical antibiotics. Catheter removal has even been performed
in a few patients in whom a diagnosis of relapsing peritonitis
was made [
12,
19]. A diagnosis of peritoneal reaction to icodextrin
is thus of great importance to avoid unnecessary manoeuvres.
It has been suggested recently that patients with sterile peritonitis secondary to icodextrin have less severe peritoneal inflammation than patients with infectious peritonitis [17]. This was supported by a weight gain, an increase in peritonitis-associated peritoneal permeability, a serum C-reactive protein level, and a leukocyte number in peritoneal dialysis effluent that were all lower in the former than in the latter group [17].
Despite this preliminary report [17], several lines of evidence suggest that sterile chemical peritonitis secondary to icodextrin is not a benign event. Several manifestations of acute peritoneal inflammation including mesothelial desquamation, presence of fibrin clusters on the peritoneal surface and oedema, together with a marked cellular infiltration of the connective tissue by lymphocytes, few polymorphonuclear neutrophils, eosinophils and mast cells were identified in the first peritoneal biopsy from a patient with a typical symptomatology [18]. Immunoperoxidase staining demonstrated that the infiltrating cells were mostly macrophages and T-lymphocytes. All these features are different from those found in bacterial peritonitis [20]. In this patient who had several bouts of sterile peritonitis, the peritoneal transport characteristics remained virtually unchanged, and the peritoneal biopsy did not show any signs of peritoneal fibrosis, suggesting that the peritoneal inflammatory lesions were acute [18]. We now have additional data on two other peritoneal biopsies (patients 3 and 4, table I in ref. 14) taken at the time of catheter removal for pleuro-peritoneal communication and renal transplantation, respectively (both patients were still be given icodextrin despite several episodes of cloudy dialysates). Varying degrees of peritoneal inflammation characterized by venulitis and/or submesothelial inflammation displaying abundant T lymphocytes and macrophages were observed, confirming the hypothesis that peritoneal inflammation of the icodextrin-associated peritonitis is not so benign. Macrophages and variable amounts of mast cells were also found throughout the interstitial peritoneal tissue. In contrast, no similar lesions, except for long-term PD changes and rare interstitial macrophages, were seen in control biopsies from two long-term PD patients on icodextrin for >2 years who never had sterile peritonitis (E. Goffin et al., manuscript in preparation).
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What is the cause of this syndrome?
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The cause of the chemical peritonitis secondary to icodextrin
has recently been identified [
21]: according to the manufacturer,
certain batches of icodextrin bags contained varying amounts
of peptidoglycan, as a contaminant. Peptidoglycans are major
components of the Gram-positive cell wall [
22]; like endotoxins,
peptidoglycans have many biological activities including the
ability to release pro-inflammatory cytokines from mononuclear
cells [
23]. This latter point is thus likely to explain both
the occurrence of cloudy dialysate effluents observed under
icodextrin and the presence of the mononuclear cell infiltration
within the peritoneal membrane.
It is of note that this theory of the peptidoglycans, although reasonable and probably acceptable, has been provided by the icodextrin manufacturer, without proof coming from independent researchers.
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Unanswered questions
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After identification of peptidoglycan as the cause of the syndrome,
all icodextrin batches suspected to contain an elevated peptidoglycan
level were recalled by the manufacturer. This recall led to
a dramatic reduction in the occurrence of sterile peritonitis,
but not its complete disappearance. For instance, the peritoneal
inflammation illustrated in
Figure 1 occurred while this patient
was given icodextrin dialysates with a peptidoglycan level below
the threshold for recall (Baxter Healthcare, personal communication).
Likewise, Enia
et al. [
16] recently reported on a patient with
an earlier history of cloudy dialysate attributed to icodextrin
presenting recurrence of abdominal discomfort and cloudy dialysate
immediately after the first use of new batch of icodextrin.
Taking this into account, it may be that some patients could
become ‘allergic’ to either icodextrin or to a small
residual amount of peptidoglycan present in the icodextrin dialysate.
This would explain some positive skin tests [
17] and the peritoneal
biopsies of our patients suggestive of a hypersensitivity reaction
[
18].
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Fig. 1. (A) Submesothelial infiltration by mono and polynuclear inflammatory cells; 190x; H&E. (B) Mast cell (arrow); 380x; Giemsa. T lymphocytes (C) and macrophages (D) are identified by indirect immunoperoxidase technique using anti-CD3 and anti-CD68 antibodies, respectively; 190x.
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Conclusions and recommendations
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Undoubtedly, the use of icodextrin in CAPD and APD patients
has numerous advantages over glucose-based dialysates including
improved ultrafiltration, better fluid control and less hypertension
[
24], decreased exposure to glucose and probably increased technique
survival. In the face of evident benefits, clinicians should,
however, be aware of the potential of icodextrin to induce chemical
sterile peritonitis. In patients in whom such a diagnosis is
plausible (by definition, dialysate culture has to be sterile),
icodextrin should be withdrawn immediately because our histology
cases did not show benign lesions. In patients in whom the icodextrin
prescription is mandatory, a re-challenge could be performed
within 2–4 weeks after the dialysate effluent has cleared.
If cloudy dialysate reappears, icodextrin must then be definitely
withdrawn. If contamination of icodextrin by peptidoglycan is
really the cause of this syndrome, the recall of contaminated
batches should be reflected by a dramatic decrease in its incidence
in the near future. Still, the use of peptidoglycan in animal
models of peritoneal dialysis, or for skin tests in ‘allergic’
patients could however put arguments forward into the debate.
This latter approach could clarify if an ‘allergic’
reaction restricted to the peritoneal membrane is the cause
of the recurrence of the symptoms in some patients and if a
therapeutic intervention could allow those patients to further
resume icodextrin infusion.
Finally, these cases illustrate the importance of the manufacturing process of peritoneal dialysis fluids given the extreme reactivity of the peritoneal membrane. They also provide new insights into the various inflammatory states that may affect the peritoneal membrane longevity.
Conflict of interest statement. None declared.
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Introduction
Clinical presentation of...