Nephrol Dial Transplant (2004) 19: 26-29
© European Renal Association–European Dialysis and Transplant Association
Editorial Comment
Flowing time on the peritoneal membrane
Michele Buemi1,
Carmela Aloisi1,
Giuseppa Cutroneo2,
Lorena Nostro1 and
Alessandro Favaloro2
1Department of Internal Medicine and 2Institute of Human Anatomy, Messina, Italy
Correspondence and offprint requests to: Prof. Michele Buemi, Via Salita Villa Contino 30, I-98100 Messina, Italy. Email: buemim{at}unime.it
Keywords: ageing; biocompatibility; peritoneal dialysis; ultrafiltration
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Introduction
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Time, passing on, rhythms our lives. This observation also applies
to physiology and pathophysiology. It is known that this seasonal
adaptability is based both on genetic programmes, and on a strict
neurovegetative and endocrinological control, with a flexible
and sophisticated network of activities changing in relation
to external stimuli and aging, starting in intrauterine life
to the years of growth, adulthood and senility. Likewise, the
peritoneum of peritoneal dialysis (PD) patients responds to
the passing of time by undergoing anatomical and functional
changes (
Figure 1).
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Fig. 1. Light microscope: 18 years old (a–b). One micrometre-thick sections, coloured with toluidine blue. Some fields show flat mesothelial cells (a); in other fields one can observe cells becoming cubic with very tight junction between them (b) (x750). 69 years old (c). One micrometre-thick section, coloured with toluidine blue. In some areas, one can notice the absence of mesothelial cells (arrow) (x750). Transmission electron microscope: 18 years old (d). Cubic cells show very tight junction between them, a normal basal membrane and microvillous (x12 500) 69 years old (e). It is possible to observe a flat cell with a thickened basal membrane and short, rare and squat microvillous (x8200).
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Although the functional characteristics of the peritoneum
in children undergoing PD are different from those in adult
patients, recent experimental studies have demonstrated that,
when adjusted in relation to body surface and age, there are
no significant differences in peritoneal fluids and solutes
transport between adults and children. In a recent study on
children under PD, time was found to have no effect on parameters
for peritoneal transport, except for the restriction coefficient
for macromolecules [
1].
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Factors involved in peritoneal ultrafiltration failure
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A large body of data demonstrates that the risk of encountering
a clinically relevant reduction in peritoneal ultrafiltration
increases in relation to the time of PD, and this risk is estimated
to be
35% after 6 years of treatment [
2]. Ambulatory PD (APD)
or continuous ambulatory PD (CAPD) modalities do not have a
significant influence on small solute transport or fluid kinetics
[
3]. Currently, four mechanisms are known to underlie failure
in peritoneal ultrafiltration [
4]. Different data demonstrate
that aquaporin-mediated water transport is altered in patients
under long-standing PD [
5,
6]. An increased peritoneal absorption
of small osmotically active solutes, followed by a dramatic
fall in the osmotic gradient, is a common and widely known mechanism
in decreasing ultrafiltration [
7]. A hypopermeable peritoneum
with loss of peritoneal surface area, typically after severe
peritonitis with adhesions, or in the case of sclerosing peritonitis,
is probably a rare mechanism of effective ultrafiltration failure.
A poor effective ultrafiltration due to high lymphatic absorption
rates is also considered of particular importance in peritoneal
aging [
8].
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Structural and functional changes of peritoneal wall
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Various morphologic and structural alterations can occur in
the peritoneal tissue, especially after long-standing PD. The
most frequently described alteration in the peritoneum of patients
on long-standing PD is the formation of a layer of collagenous,
acellular material replacing the mesothelial surface. The peritoneum
of patients with this type of alteration contains groups of
cells exposed to degenerative phenomena, including intracellular
oedema, destruction and degeneration of cytoplasmic structures
and large areas of peritoneal denudation among mesothelial cells,
which are still intact [
3]. Also, mesothelial cell cultures
with long-standing exposure to glucose solutions undergo early
degenerative alterations, such as hypertrophy, intracellular
oedema, cell cycle arrest, early aging and death. During CAPD,
mesothelial cells undergo epithelial-to-mesenchymal transition
[
9]. These cells differ greatly from non-exposed mesothelial
cells, in morphology and probably in function, with a strongly
accelerated life cycle [
10,
11]. Reduplication and thickening
of the basal mesothelial membrane have also been described in
the peritoneum of patients on long-standing PD, and these alterations
are similar to those described in patients with diabetes mellitus.
The membrane, some areas of which appear fragmented, is made
up of bands of collagen and rectiform elastic lamina within
an amorphous matrix [
12]. An increase in the fibrotic processes
of the sub-mesothelial layers is a typical finding in a peritoneum
with long-standing exposure to hypertonic glucose solutions.
However, before dialysis is started, a significant thickening
of the sub-mesothelial space is present in patients with pre-terminal
uraemia. This thickening is similar to that found in peritoneal
biopsies of patients who undergo haemodialysis before switching
to PD. In their study on rat peritoneum, Combet
et al. [
13]
demonstrated that such alterations are more significant 6 weeks
after induction of a uraemic status compared with 3 weeks. Each
structural alteration has different functional consequences
[
14]. Sub-mesothelial and perivascular fibrosis increases the
distance between endothelium and dialysate, thus increasing
permeability to small solutes. The increased peritoneal permeability
observed in uraemic rats appears to depend more on vascular
proliferation than on fibrosis. The increased expression of
angiogenic factors VEGF and FGF2 at the third week of induction
of uraemia suggests that these growth factors are involved in
neovascularization and in the fibrotic alterations observed
at 6 weeks [
13]. Nitric oxide (NO) is essential for the biological
activities of VEGF, and an increased expression of both these
mediators could cause the increased vascularization found in
the peritoneum of patients on long-standing PD [
15]. The data
suggest that uraemia itself can induce anatomical changes in
the peritoneal membrane before dialysis is started, and these
alterations may depend on the chronic inflammatory status typical
of this condition.
The important changes in the structure of the peritoneal vessels described in PD patients, similar to those observed in patients with diabetic microangiopathy, include: reduplication of the basal capillary membrane, expansion of the extracellular matrix within the middle arteriolar sheath and type IV collagen deposits in the arteriolar walls. Several authors have found a link between loss of ultrafiltration and the severity of lesions, and suggest that vascular alterations depend on the production, and depositing, of advanced glycosylation products, AGE [16]. Williams et al. [17] found vasculopathy in 20% of peritoneal biopsies obtained from uraemic patients, not on PD. The percentage of patients with vasculopathy increases in parallel with the duration of PD; after 6 years of treatment, 87% of biopsies present clear signs of vascular damage.
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Potential therapeutic strategies
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A better understanding of these mechanisms should yield new
therapeutic strategies aiming to protect the peritoneal membrane
from the consequences of long-term PD [
18]. Pharmacological
strategies should aim to reduce RCO and AGE formation in the
dialysate through solutions other than glucose and heat-sterilized
ones, or through AGE formation inhibitors or
L-arginine–NO
pathway inhibitors, using
L-arginine analogues. Another possible
therapeutic strategy might consist of modulating angiogenesis
using agents that inhibit endothelial cell growth, adhesion
and cell migration, or that interfere with vascular growth factors
VEGF and ßFGF, or their receptors. The potential benefit
of the above treatments should be carefully evaluated, as the
inhibition of multifunctional mediators, such as NO, could be
a double-edged sword. Moreover, there are only few trials using
anti-angiogenic compounds in patients with non-neoplastic diseases,
and there is little information on the safety and long-term
effects of this treatment on normal physiological processes
[
19].
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Future perspectives
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New perspectives in treatment and prevention of ultrafiltration
failure are offered by gene therapy, to preserve the structure
and function of the peritoneal membrane. Peritoneal mesothelial
cells or peritoneal leukocytes can be modified to express anti-
inflammatory cytokines, as interleukin-1 receptor antagonist
(IL-1RA), the soluble receptor to TNF
and IL-10. Membrane integrity
could be preserved enhancing the expression of fibrinolytic
factors (tissue plasminogen activator, tPA) and anti-fibrotic
molecules that counteract VEGF action and inhibit nuclear factor
kappa B (NF-
B) and transforming growth factor ß (TGF-ß)
[
20] (
Figure 2).
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Fig. 2. Ultrafiltration failure results from RCOs and glucose-derived substances action through neovascularization. PD fluid RCOs are lowered in non-glucose fluids or in multicompartment bag-systems. Circulation RCOs metabolism is enhanced through reductive reactions. RCOs are trapped by specific adsorbents and their action on available vascular surface area is inhibited by anti-angiogenesis substances, NOS inhibitor, NO scavenger. Multiple therapeutic approaches should be promoted to preserve peritoneal membrane structure and function.
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Conclusion
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The peritoneum, with its simple structure but complex role,
undergoes tissue damage as a consequence of different diseases.
New therapeutic possibilities, respecting its morphology, will
improve the maintenance of normal function over time.
Conflict of interest statement. None declared.
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Introduction
Factors involved in peritoneal...