Perit Dial Int
29(Supplement_2):
195-197
2009
© 2009 International Society for Peritoneal Dialysis
Part 7: Protection of Peritoneal Membrane |
KARL D. NOLPH STATE OF THE ART LECTURE: FEASIBLE AND FUTURE OPTIONS FOR SALVATION OF THE PERITONEAL MEMBRANE
Raymond T. Krediet1,
Annemieke M. Coester1,
Inna Kolesnyk1,
Marijke de Graaff1,
Machteld M. Zweers1,
Watske Smit1,2 and
Dirk G. Struijk1,2
Division of Nephrology,1 Department of Medicine,
Academic Medical Center, University of Amsterdam, and Dianet
Foundation,2 Utrecht–Amsterdam, Amsterdam,
Netherlands
Correspondence to: R.T. Krediet, Room F4-215, Academic Medical Center,
Division of Nephrology, Department of Medicine, PO Box 22700, Amsterdam 1100
DE Netherlands.
C.N.deboer{at}amc.uva.nl
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ABSTRACT
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A review is given of the various available strategies that can be used
to protect the peritoneal membrane. A discussion of experimental studies on
approaches that are still experimental, but that might be applied in patients
in the future, follows. The currently available approaches include dietary
sodium restriction, use of high-dose loop diuretics and of inhibitors of the
renin–angiotensin system. All should preferably be combined with a
dialysis prescription aimed at reducing the patient's exposure to glucose and
its degradation products. The experimental studies indicate favorable effects
of combining osmotic agents, together with drugs that interfere with the
polyol pathway and the formation of advanced glycosylation
end-products.
KEY WORDS: Biocompatibility; ACE inhibitors; osmotic agents.
Many studies have shown that, as compared with hemodialysis patients,
patients on peritoneal dialysis (PD) have a survival advantage during the
first years of dialysis (1).
The development of functional and morphologic alterations of the peritoneal
membrane in some long-term patients is one of the reasons that the initial
survival advantage is lost. Ultrafiltration failure is the most important
functional abnormality. It occurs in one third of long-term PD patients and is
most often caused by a combination of fast transport of low molecular weight
solutes, leading to a rapid disappearance of the osmotic gradient and a
reduced osmotic conductance to glucose. This situation leads to impaired free
water transport.
Many morphologic abnormalities can develop. These include neoangiogenesis
with diabetiform arteriolar changes and venular subendothelial hyalinosis. In
addition, loss of mesothelium and marked fibrosis are often present. Long-term
exposure to conventional dialysis solutions is the most likely explanation for
the foregoing abnormalities. Glucose, lactate, and glucose degradation
products (GDPs) all especially contribute to bioincompatibility. The objective
of the present review is to discuss feasible strategies to prevent alterations
in peritoneal transport and the peritoneal membrane, and also to focus on
future approaches that are promising for salvation of the peritoneal
membrane.
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FEASIBLE STRATEGIES TO PREVENT FUNCTIONAL AND MORPHOLOGIC ALTERATIONS IN THE PERITONEAL MEMBRANE
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Strategies that can be applied to prevent alterations in the peritoneal
membrane include a reduction in exposure to high dialysate glucose
concentrations, a reduction in exposure to GDPs, and medical treatment.
Peritoneal exposure to glucose and GDPs can be lower with higher urine
production and better preservation of the glomerular filtration rate (GFR).
Urine production can be increased with the regular use of loop diuretics in
high dosages—for instance, furosemide 500 mg daily. This treatment also
increases sodium and potassium removal, but has no effect on GFR or clearance
of urea. It also has no effect on the downward time course of the GFR. The
latter can be influenced by treatment with angiotensin converting-enzyme (ACE)
inhibitors. These drugs also reduce thirst. Dietary sodium restriction should
be prescribed as well, not only because of its effect on thirst, but also
because it leads to a reduction of blood pressure in many patients. The use of
icodextrin for the long dwell, especially in combination with replacement of a
short 1.36% glucose dwell by a dwell with an amino-acid-based solution,
reduces exposure to glucose and GDPs by 68% on average in a conventional
continuous ambulatory PD (CAPD) schedule.
Temporary discontinuation of PD for 1 month in patients needing treatment
with 3.86% glucose solutions because of ultrafiltration failure may restore
ultrafiltration, especially when the interval between the development of this
complication and the start of peritoneal rest is short. Exposure to GDPs can
be reduced by replacing conventional dialysis solutions with the so-called
biocompatible ones that all have low GDP concentrations. These solutions vary
in pH and buffer substance. In vitro experiments have shown improved
cell viability for all biocompatible solutions. A
bicarbonate/lactate–buffered solution led to less neoangiogenesis and
fibrosis in a 20-week peritoneal exposure model in the rat. Clinical studies
have shown less pain after instillation of this fluid. For some solutions, a
slight decrease in plasma concentrations of advanced glycosylation
end-products (AGEs) has been found. The clinical importance of this finding is
unknown. Studies of possible effects on residual renal function have been
equivocal, but a randomized controlled trial with a follow-up of 1 year showed
no effect on residual GFR of exposure to biocompatible fluids
(2). Long-term treatment with
bicarbonate/lactate–buffered solutions was not associated with an
increase of low molecular weight solute transport during follow-up. However,
in all studies, an increase in effluent cancer antigen 125 was found, which
suggests an increase in mesothelial cell mass. All experimental and clinical
studies with biocompatible solutions have shown beneficial effects as already
discussed. Inferiority to conventional solutions has never been described. The
use of these "biocompatible" solutions should therefore be part of
a strategy aimed at minimizing peritoneal damage and preserving the peritoneum
as a dialysis membrane.
Medical treatment that can be applied in patients to preserve the
peritoneum mainly consists of interventions in the renin–angiotensin
system. Angiotensin II has growth factor properties and is involved in the
effects of transforming growth factor beta. Experimental studies in rat models
showed that the use of ACE inhibitors markedly attenuated the morphologic
abnormalities induced by 3.86% and 4.25% glucose-based dialysis solutions.
Analyses were therefore conducted in two prospective observational studies. A
single-center study in 66 patients on PD for at least 2 years, in which 36
used an ACE inhibitor or an angiotensin II receptor blocker (ARB), showed an
absence of an increase in the mass transfer area coefficient of creatinine
with the duration of PD, but no effect on ultrafiltration parameters
(3). These results have been
confirmed in an analysis of the cohort from the Netherlands Cooperative Study
on the Adequacy of Dialysis for 24-hour dialysate-to-plasma (D/P) creatinine.
Either ACE inhibitors or ARBs (or both) were used in 120 of 217 CAPD patients
who were treated with PD for at least 2 years. The control group showed an
increase of D/P creatinine during follow-up, which was attenuated in the group
treated with ACE inhibitors or ARBs. No differences were found between the
patients on ACE inhibitors and on ARBs. It can be concluded from the foregoing
data that preservation of residual GFR and of peritoneal membrane function can
be considered new indications for treatment with ACE inhibitors and ARBs in
addition to the usual indications, such as hypertension, heart failure, and
reduction of thirst.
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FUTURE APPROACHES FOR SALVATION OF THE PERITONEAL MEMBRANE
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All investigations discussed next have been conducted in the chronic
peritoneal exposure model in rats
(4). In brief, Wistar rats are
implanted with a subcutaneous access device (Rat-o-Port: Access Technologies,
Skokie, Illinois, U.S.A.) in the neck. A silicone catheter (1.1-mm lumen) is
attached and tunneled subcutaneously over the left flank into the peritoneal
cavity proximal of the umbilicus. After a recovery period of 1 week, daily
infusion of dialysis solutions (60 mL/kg body weight) are started in awake
animals and continued for 20 weeks. At that time, a standard peritoneal
permeability analysis (SPARa) is performed, after which the animals are
humanely killed to obtain peritoneal tissue for assessment of morphology. As
compared with exposure to a Ringer's lactate solution, exposure to a
conventional 3.86% glucose dialysis solution was associated with a large
number of vessels, with diabetiform alterations and increased fibrosis in the
peritoneum. These alterations were very similar to those seen in some
long-term PD patients. As discussed earlier, exposure to a
bicarbonate/lactate–buffered neutral-pH glucose solution, and also to
icodextrin solution, was associated with less angiogenesis and fibrosis than
were seen with a 3.86% glucose solution.
Intracellular breakdown of glucose in the glycolysis chain leads to an
increase in the NADH/NAD+ ratio, which is also present during
hypoxia. Hypoxia is a potent stimulus for the formation of vascular
endothelial growth factor, which is involved in neoangiogenesis. This
phenomenon, induced by glucose, has also been called pseudohypoxia. In a
normal situation, the increase in the NADH/NAD+ ratio is partly
counteracted by conversion of pyruvate to lactate. During this reaction NADH
is used, and NAD+ is formed. When high intracellular lactate
concentrations are present, the reaction may reverse, thereby contributing to
the severity of pseudohypoxia and neoangiogenesis. These events might explain
why long-term exposure to a biocompatible bicarbonate/lactate–buffered
solution reduced the number of peritoneal vessels as described earlier,
because that solution contains less lactate than conventional solutions do. As
a proof of principle, a pyruvate-buffered solution attenuated the increase in
peritoneal vessels. It also reduced the plasma
betahydroxy-butyrate/acetoacetate ratio, which points to a lower
NADH/NAD+ ratio during pyruvate exposure
(5). Despite these encouraging
results, the use of pyruvate-buffered solutions is hampered by practical
problems.
No single osmotic agent can fully replace glucose for all exchanges.
Therefore, combinations of various osmotic agents are a logical approach. An
experimental solution called GLAD consists of a combination of osmotic agents
in a bicarbonate/lactate buffer. The osmotic agents are glycerol (1.4%), amino
acids (0.5%), and dextrose (1%). This solution was tested in our long-term
animal model, in which chronic renal failure was induced by a one-step 70%
nephrectomy. Daily exposure to GLAD for 16 weeks was associated with a marked
reduction in the number of vessels and the amount of peritoneal fibrosis.
Clinical studies are required for confirmation of these very promising
results.
Drugs that are of potential interest in reducing the development of
peritoneal abnormalities include inhibitors of the polyol pathway and agents
that influence the formation of AGEs. The rationale for investigating the
effects of polyol pathway inhibitors is the intracellular degradation of
glucose. In the presence of high intracellular glucose concentrations, the
degradation of glucose occurs not only by glycolysis, but also in the polyol
pathway. In the latter pathway, aldose reductase is required to convert
glucose into sorbitol. This step is followed by the formation of fructose from
sorbitol. Glycolysis and the polyol pathway both increase the
NADH/NAD+ ratio. Aldose reductase inhibitors lead to less NADH
formation in the polyol pathway. An aldose reductase inhibitor, zopolrestat,
was administered orally in rats that were exposed to a conventional 3.86%
glucose solution. The zopolrestat group showed attenuation of the formation of
peritoneal vessels and fibrosis induced by the dialysis solution. Similar
results were obtained with the administration of aminoguanidine, which is an
inhibitor of AGE formation. The effects of the AGE crosslink breaker ALT-711
were similar to those of aminoguanidine.
At present, because of side effects, none of the drugs investigated can be
used in patients. However, it is conceivable that new drugs with similar
beneficial effects and fewer side effects will be developed.
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CONCLUSIONS
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Many strategies, all of which can be combined, are available for salvation
of the peritoneal membrane. These include prescription of dietary sodium
restriction and use of high-dose loop diuretics and of ACE inhibitors and
ARBs. These measures should preferably be used in addition to a dialysis
schedule consisting of biocompatible solutions, with icodextrin for the long
dwell and one exchange with amino acids. Based on the results of experimental
studies, future options should include dialysis solutions with a combination
of osmotic agents, together with drugs that interfere with the polyol pathway
and the formation of AGEs.
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REFERENCES
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ABSTRACT
FEASIBLE STRATEGIES TO PREVENT...
