Perit Dial Int
29(2):
135-141
2009
© 2009 International Society for Peritoneal Dialysis
THE JOHN F. MAHER AWARD RECIPIENT LECTURE 2008 |
APPLYING TRANSLATIONAL RESEARCH IN UNDERSTANDING COMPLICATIONS AND DEFINING TARGETS FOR INTERVENTION: INFLAMMATION IN PD AS A MODEL
Roberto Pecoits–Filho
Center for Health and Biological Sciences, Pontifícia Universidade
Católica do Paraná, Curitiba, Brazil
Correspondence to: R. Pecoits–Filho, Center for Health and Biological
Sciences, Imaculada Conceição, 1155, Curitiba, PR 80215-901
Brazil.
r.pecoits{at}pucpr.br
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ABSTRACT
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The bench-to-bedside approach to translational research is becoming
increasingly important to efficiently advance understanding of the mechanisms
underlying disease and to improve the quality of patient care. Although this
investigation model has been practiced since the early days of the therapy,
robust research platforms built to practice translational research have only
recently been structured in the field of peritoneal dialysis. Experience with
a translational research environment that generated most of the information
cited in this overview is the core of this manuscript. The central
investigation theme described is how to approach the cardiovascular
complications of peritoneal dialysis. The research question was, could the
continuous activation of inflammatory pathways be central in this process and
represent a relevant target for interventions?
KEY WORDS: Inflammation; cardiovascular disease.
In order to have an impact in improving human health, scientific
discoveries must reach clinical applications. Such discoveries typically begin
at "the bench" with basic research in which scientists study
disease at a molecular or cellular level, then progress to the clinical level,
or the patient's "bedside." Scientists and clinicians are
increasingly aware that this bench-to-bedside approach to translational
research is really a two-way road: clinical researchers make novel
observations about the nature and progression of disease that often stimulate
basic investigations, and basic scientists provide clinicians with new tools
for use in patients and for assessment of their impact. The most important
part of the definition of translational research is the focus on potential
clinical application. Translational research has proved to be a powerful
process that drives the clinical research engine; however, a stronger research
infrastructure, close interaction, and global collaboration could strengthen
and accelerate this critical part of the clinical research enterprise.
Although this investigation model has been practiced since the early days
of the therapy, research platforms built to practice translational research
have only recently been structured in the field of peritoneal dialysis (PD).
Experience with a robust translational research environment that generated the
information cited in this overview is the core of this manuscript. The central
investigation theme was how to approach the cardiovascular (CV) complications
of PD, and the research question was, could the continuous activation of
inflammatory pathways be central in this process? The four steps in the
translational process are briefly described and illustrated with basic
references from our research group.
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STEP 1: BUILDING UP A RATIONALE — INFLAMMATION MAY BE DRIVING A SIGNIFICANT PROPORTION OF THE CV COMPLICATIONS OF CHRONIC KIDNEY DISEASE (CKD) AND LONG-TERM PD
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Cardiovascular disease represents the main cause of death in PD patients in
most published studies, including a recent very large Brazilian PD cohort
study (1). However, the
mechanisms mediating the increased CV risk observed in this group of patients
are still largely unknown, which limits the perspective of effective
therapeutic strategies (2). The
leading hypothesis that tries to explain the high CV risk observed in PD
patients is that they are exposed to a number of traditional risk factors
already at the onset of their CKD, since many of these risk factors are common
to both CV disease and CKD (3).
Risk factors related to CKD are introduced during the progression of renal
dysfunction, changing the profile of both the risk factors and the mechanisms
behind CV disease. During this phase — usually starting when the
glomerular filtration rate is below 60 mL/minute — the list of risk
factors is enriched with disturbances of mineral metabolism, anemia, fluid
overload, uremic toxicity, and increased signs of oxidative stress and
inflammation (4). Although many
of the risk factors linked to CV burden are not related to the dialytic
procedure, there is the potential for additional harm, related to the dialysis
fluids, being introduced after the initiation of PD: directly due to
bioincompatibility of dialysis solutions and indirectly through absorption of
glucose (5). The presence of
the PD catheter and the risk of subclinical infection may also contribute to
the low-grade systemic inflammation observed in PD patients, although there
are not sufficient data to support this hypothesis.
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STEP 2: SEARCHING FOR CONSISTENT BACKGROUND INFORMATION THAT MAY JUSTIFY THE HYPOTHESIS THAT INFLAMMATION PLAYS A CENTRAL ROLE IN CV COMPLICATIONS OF CKD
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Awareness of the mechanisms underlying CV disease have shifted recently to
include inflammation and oxidative stress as pivotal factors determining the
initiation and progression of CV disease in CKD patients. In addition, the
vascular endothelium, once considered a barrier between intravascular and
interstitial compartments, is nowadays considered much more than an inert,
single-cell lining covering the internal surface of blood vessels. Under
normal conditions, the endothelium actively decreases vascular tone, inhibits
cell adhesion and aggregation, limits activation of the coagulation system,
and stimulates fibrinolysis. Another fundamental function of the healthy
endothelium is to keep vascular permeability tightly controlled. Several
factors induce vascular damage, which leads to a change in endothelial cell
phenotype characterized by impaired nitric oxide production, altered smooth
muscle cell relaxation and proliferation, reduced angiogenesis, activation of
coagulation, and increased cell adhesion to the vascular wall. Atherosclerotic
CV disease is initiated and perpetuated by the interaction of immune cells
with cells of the vessel wall, mediated by inflammatory mediators, namely
chemokines and adhesion molecules. There is increasing evidence being
generated from experimental and clinical studies that these early stages of
atherosclerosis are extremely important. This is clear from experimental
models of CKD-related CV disease, namely the 5/6 nephrectomized ApoE knockout
mice. In the animal model, the presence of renal dysfunction not only enhances
and accelerates the atherosclerotic process through overexpression of those
mediators of inflammation, but it also changes the profile of the lesion,
which is characterized by intense calcification and oxidative stress [reviewed
in Ref. (4)]. In addition,
prospective clinical data strongly suggest that endothelial activation,
oxidative stress, and inflammation occur early in the atherosclerotic process,
and that elevated serum levels of biomarkers of inflammatory and oxidative
stress are present in a large proportion of CKD patients, including children
(6) and adults
(7) with CKD in all stages.
Other sources of stimulating data linking inflammation to CV complications
in CKD are based on genetic studies, particularly association studies using
single nucleotide polymorphisms (SNPs). Although the nephrology community has
only recently started to investigate the impact of various gene polymorphisms
in inflammation and oxidative stress-related genes, there is evidence
suggesting that genetic variation may indeed affect the phenotype of this
patient group. At present, tumor necrosis factor alpha 308, interleukin
(IL)-6-174 and IL-10-1082 SNPs seem to be most consistently associated with
adverse clinical outcomes in CKD and PD patients
(8). Moreover, there are
reports suggesting that genetic variations in genes related to oxidative
stress [myeloperoxidase (9) and
NADPH (10)] are associated
with important clinical features in the CKD population. Altogether, these data
reinforce that individuals with a genetic predisposition to present an
exaggerated inflammatory response to stimuli may be exposed to a high risk of
developing CV complications in CKD.
Back to the clinical ground, since the first report by Bergström and
his co-workers of an association between elevated C-reactive protein (CRP; a
marker of systemic inflammation) and increased mortality in CKD patients,
several groups have reported almost identical findings in different patient
groups, in all stages of CKD, and using other markers of inflammation
(11). Although the association
between single or multiple
(12) measurements of
inflammation markers and an increased risk of mortality in CKD patients is a
consistent finding, the triggers of the inflammatory response are still only
superficially understood. In addition, whether inflammation is a direct
causative factor determining target organ damage or represents an
epiphenomenon is still an unanswered question. Direct uremic toxicity,
accumulation of modified proteins (such as advanced glycation end-products),
retention of inflammatory mediators, mechanical stress of the vascular wall as
a result of hypertension, comorbidities such as advanced age and diabetes, and
disorders of mineral metabolism and anemia are examples of factors potentially
triggering the inflammatory response but are unrelated to dialysis treatment
(13).
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STEP 3: REBUILDING THE RATIONALE WITH A FOCUS: THE IMPORTANCE OF INFLAMMATION IN CV COMPLICATIONS OF PD
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Although systemic inflammation is enhanced even before the initiation of
dialysis therapy, the dialysis procedure per se potentially induces
additional inflammatory activity. However, upon the introduction of PD, some
other inflammation- and oxidative stress-inducing factors are added to that
list (14). Therefore, high
glucose concentration and glucose degradation products present in the
dialysate, transient intraperitoneal acidosis, and intraperitoneal
inflammation and oxidative stress as a response to bioincompatibility of
solutions have to be considered potential additional causes of peritoneal and
systemic inflammation and oxidative stress. The metabolic and body composition
changes due to glucose reabsorption also create a proinflammatory milieu
through the generation of central adiposity, insulin resistance, and
dyslipidemia. The impact of those reactions not only enhances the inflammatory
status but also may change the profile of the immune response and its
consequences (5).The sequence
of inflammatory events and mechanisms in the PD patient are described in the
following subsections.
Inflammation and the Peritoneal Membrane: Inflammatory changes
such as increased numbers of macrophages are often seen in the peritoneum of
CKD patients. There are consistent data coming from the Peritoneal Biopsy
Registry showing that morphological changes are already present before the
initiation of PD. Experimental studies confirm that induction of CKD or
diabetes can alter the structure and function of the peritoneal membrane not
exposed to PD fluids. In addition, peritoneal changes are enhanced with time
on PD. This is true even in the absence of peritonitis, indicating that the
peritoneum of PD patients is a chronically inflamed organ. Observations of
peritoneal tissue from long-term PD patients (and in experimental studies)
show a thickening of the submesothelial space and alterations of the
microvessel structure [reviewed in Ref.
(14)].
These morphological alterations occur concomitantly with functional changes
and, over time, both increase peritoneal small-solute transport rate (PSTR).
For reasons yet to be clarified, a high PSTR has been identified as an
important cause of PD technique failure and, at least in patients under
continuous ambulatory PD, represents an independent risk factor for increased
mortality in PD. This may be linked to the diminished ultrafiltration capacity
during long dwells and may not be true for patients on automated PD.
Interestingly, we observed that patients with high PSTR presented higher
plasma levels of IL-6 and higher prevalence of comorbidities such as diabetes
mellitus and peritonitis (15).
Also, in a longitudinal study, intraperitoneal inflammation was associated
with high PSTR, but this association was observed predominantly during the
early phase of PD (16).
Patients with a high PSTR from the beginning of the therapy are typically
inflamed and have a high prevalence of comorbidities and high mortality
(15). In addition, these
patients sometimes present peritoneal albumin leakage, which may reflect
endothelial dysfunction (17).
On the other hand, patients presenting the "late acquired type" of
high PSTR develop high PSTR over time on PD, due primarily to structural
changes in the peritoneal membrane caused by continuous exposure to high
glucose PD solutions. These patients do not necessarily have a higher
prevalence of inflammation or comorbidities, and the high mortality could be
prevented by correcting fluid overload
(14).
Bioincompatibility of PD Solutions and Inflammation: One potential
risk factor for inflammation in PD patients may relate to prolonged exposure
to conventional bioincompatible glucose-based PD solutions, that is, solutions
that have high osmolarity, glucose, and lactate concentrations, low pH, and
high content of glucose degradation products, which enhance the formation of
advanced glycation end products.
Many biomarkers of intraperitoneal inflammation have been studied in the
clinical setting. We concentrated our studies on the analysis of
intraperitoneal IL-6 because its levels are stable in dialysate, the
concentration is many-fold higher than in plasma, and the available methods
are simple and reproducible
(18). However, it must be
emphasized that there is no consensus about the ideal biomarker in this area.
It is noteworthy that, although IL-6 is a well-recognized marker of systemic
inflammation (19), the precise
significance of intraperitoneal IL-6 in the setting of PD is still under
investigation. It is also important to note that in vitro studies
that show IL-6 levels after stimulation reflect cell vitality
(18). After such stimulation,
the use of more biocompatible solutions is usually associated with higher IL-6
production. In clinical studies, IL-6 levels should represent the effect of
local stimulation of IL-6 production, and thus the degree of intraperitoneal
inflammation. Dialysate IL-6 increases over time in patients using standard
glucose-based PD solutions, and IL-6 effluent levels are related to peritoneal
transport and markers of oxidative stress and neoangiogenesis
(16). Moreover, in one
interventional study, IL-6 levels in the dialysate effluent decreased when
patients were shifted to more biocompatible solutions, suggesting less
intraperitoneal inflammation with the use of those solutions
(20). In addition, an
association was found between systemic and intraperitoneal inflammation based
on the correlation between plasma and dialysate IL-6 levels
(16), although this finding
needs to be confirmed in larger studies.
Taken together, the available data suggest that PD solutions may induce
intraperitoneal inflammation, and the generation of a cellular response in the
peritoneal cavity may affect systemic inflammation. Whether systemic
inflammation causes local inflammation and/or intraperitoneal inflammatory
activation leads to a systemic response requires further evaluation. Also, the
impact of intraperitoneal inflammation on CV risk remains to be
investigated.
Fluid Overload and Inflammation: Volume overload is a frequent
complication in PD patients and may itself be associated with immune
activation. This activation may occur because of bacterial or endotoxin
translocation in patients with severe gut edema as a result of severe volume
overload, which in turn may lead to increased production of proinflammatory
cytokines (21). Indeed, we
showed that CKD patients with signs of fluid overload present higher
circulating endotoxin levels
(22). A recent study found
that endotoxemia is common in PD patients and that the degree of circulating
endotoxemia might be related to the severity of systemic inflammation and
features of CV disease. These results suggest that endotoxemia may play a
contributory role in the systemic inflammatory state and accelerated CV risk
in PD patients. In summary, fluid overload is common among PD patients and may
potentially be an important modifiable contributor to inflammation
and CV risk among PD patients.
Altered Carbohydrate Metabolism, Body Composition, and
Inflammation: Carbohydrate metabolism is severely altered in CKD, even
before the initiation of PD. Nondiabetic patients with CKD often have mild
fasting hyperglycemia and abnormal glucose tolerance, although most patients
can maintain normoglycemia at the expense of hyperinsulinemia. Particularly in
PD patients using glucose-based solutions, systemic glucose load may have an
impact on the disorders described above
(5). Indeed, there is
increasing concern about the adverse systemic effects of absorbed glucose,
especially with respect to the CV risk profile. Interestingly, we recently
described a state of insulin resistance, mild increase in fasting glycemia,
dyslipidemia, altered glycated hemoglobin (HbA1c), and inflammation in a group
of nondiabetic PD patients that was markedly worse in PD than in hemodialysis
patients (23). These
preliminary data point to a complex metabolic disorder of carbohydrate
metabolism present in PD patients, a disorder that might have potential
effects on the CV system.
The mechanism by which altered carbohydrate metabolism may lead to an
increase in CV risk is only recently being understood, but emerging evidence
points to an important role for the central obesity–insulin
resistance–inflammation axis. Several studies have demonstrated that fat
tissue, particularly the visceral fat accumulated in central obesity, is
immunologically active and it is able to attract macrophages and initiate a
process of production of inflammatory mediators that ultimately lead to
insulin resistance, hepatic steatosis, and accelerated atherogenesis. Added to
hypertension, dyslipidemia, and central obesity — all common features of
PD patients — a metabolic syndrome (a cluster of risk factors related to
increased morbidity and mortality in the general population) potentially
develops in a high proportion of these of patients. In a recent
cross-sectional study, we observed that 53% of our PD patients filled the
criteria for metabolic syndrome, a proportion that was significantly higher
than that observed in hemodialysis patients
(23). Accordingly, we observed
in a large cohort of dialysis patients that high plasma levels of monocyte
chemoattractant protein-1 (a central mediator of the early atherogenic
response) were significantly associated with hypertension, abdominal
circumference, homeostasis model assessment (HOMA) index, and fasting glucose.
Although there is no description of the impact of a metabolic syndrome on
clinical outcome in PD patients, a few studies have described the relationship
between abnormal fasting glycemia and HbA1c and increased mortality in groups
of nondiabetic patients. Based on these observations, we hypothesize that the
continuous absorption of glucose during PD will lead to a progressive increase
in central fat accumulation, inducing a worsening of insulin resistance,
hepatic steatosis, and endothelial dysfunction, as well as leading to an
increase in the concentration of plasma adhesion molecules, chemokines, and
surrogate markers of inflammation. Those inflammatory mediators will
orchestrate organ damage in the vascular wall as well as in other target
organs.
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STEP 4: BACK TO THE PATIENT
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Although inflammation has been consistently recognized as a strong risk
factor for CV disease in CKD patients, anti-inflammatory treatment strategies
have yet to be proved effective in reducing morbidity and mortality. However,
a number of potential treatment strategies, both related and unrelated to
dialysis treatment, have been proposed. To date, five classes of drugs are of
particular interest: HMG-CoA reductase inhibitors (statins), sevelamer,
angiotensin-converting enzyme inhibitors (ACEi), peroxisome proliferator
activated receptor (PPAR) agonists, and antioxidative agents (such as vitamin
E and n-acetylcysteine). Also, there is growing evidence that the use of
vitamin D analogs may reduce inflammation and protect the CV system. An
overview of potential pharmacological strategies described in the following
paragraphs is summarized in Ref.
(2).
Statins have consistent background information generated from studies in
the general population pointing to a reduction in CV risk
(24). Ongoing trials that will
be finished in the near future may answer the question of whether statins will
be universally applied to reduce risk in dialysis patients, since the results
of the 4D Trial were not positive. There is an urgent need to perform trials
with statins in the PD population, in which dyslipidemia is more prevalent and
severe.
Angiotensin-converting enzyme inhibitors may prove beneficial in reducing
inflammation and CV disease in CKD patients. Clearly, the
renin–angiotensin system may contribute to inflammatory processes within
the vascular wall and contribute to the development of plaque instability and
acute coronary syndromes. Inhibiting the formation of angiotensin II by ACEi
and angiotensin II blockers may reduce the damaging effects on endothelial
function, vascular smooth muscle cells, and inflammatory processes.
Preliminary data in PD are promising
(25), but prospective studies
will determine if ACE inhibition may lead to a decrease in CV mortality in PD
patients.
Although studies in the nonrenal population have failed to show that
vitamin E supplementation improves CV outcomes, it is reasonable to speculate
that populations exposed to high levels of oxidative stress, such as
malnourished and inflamed CKD patients, would benefit the most from
antioxidant intervention. Indeed, in the CKD population, the SPACE study
(26) demonstrated a reduction
in myocardial infarction and other CV events (but not overall mortality) in
the vitamin E-treated group compared to patients receiving placebo. Moreover,
a recent study (27) showed
that n-acetylcysteine (a thiol-containing antioxidant) reduces composite CV
end points in hemodialysis patients.
The insulin-sensitizing thiazolidinediones, which are selective ligands of
the nuclear transcription factor PPAR
, are the first drugs to address
the basic problem of insulin resistance. PPAR is expressed most
abundantly in adipose tissue but is also found in pancreatic beta cells,
vascular endothelium, and macrophages. Rosiglitazone is a PPAR agonist
that has anti-inflammatory properties and was administered to type 2 diabetes
patients undergoing PD. There was a significantly greater decrease in insulin
dosage in the treatment group compared to the control group. At the end of the
study, patients treated with rosiglitazone also had significantly lower CRP
levels than the control group
(28). Whether long-term use of
rosiglitazone reduces CV risk needs further investigation.
Finally, the impact of low glucose regimens, different electrolyte
compositions, better ultrafiltration capacity, and alternative solutions with
a better biocompatibility profile will need to be analyzed in the clinical
setting to test the hypothesis that they can reduce CV mortality in PD
patients (7). Background
results from animal studies, small interventions leading to a reduction of
surrogate markers, and relatively large cohort studies are stimulating but
large randomized controlled trials designed to reduce CV end points and,
ultimately, mortality are lacking. The PD community needs to join forces to
induce these studies, which are expensive and hard to perform but are
absolutely necessary to advance the knowledge of how to manage these
patients.
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SUMMARY AND CONCLUSIONS
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The overview of published data presented in this manuscript displays an
example of the translational research approach to one of the most important
challenges in PD therapy at the moment: to advance the understanding of
mechanisms behind CV complications in PD patients
(Figure 1). It is hoped that
this work will challenge the way we treat our patients today and will
contribute to improvements in PD treatment in the future.
View larger version (11K):
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Figure 1 — Schematic approach to the relationship between chronic kidney
disease (CKD)-induced inflammation and cardiovascular (CV) disease in
peritoneal dialysis (PD) patients. Apo = apolipoprotein; KO = knockout; NAC =
n-acetylcysteine; SNPs = single nucleotide polymorphisms; PSTR = peritoneal
small-solute transport rate; PPAR = peroxisome proliferator activated
receptor; ACEi = angiotensin-converting enzyme inhibitor; UF =
ultrafiltration.
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DISCLOSURE
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The author received honoraria from Baxter and Gambro to participate in
educational programs. He participated in advisory boards with Roche, Genzyme,
and Baxter. He also received research grants from Astra Zeneca, Roche, and
Amgen.
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ACKNOWLEDGMENTS
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Studies cited in this manuscript were supported by funds obtained by the
Division of Renal Medicine and Baxter Novum, Department of Clinical Science,
Karolinska University Hospital Huddinge, Sweden, from the Brazilian Funds for
Scientific Support (CNPq) and from Fundação Araucária of
Paraná State.
The author thanks the research group from the Karolinska Institute (Bengt
Lindholm, Peter Stenvinkel, Bjorn Anderstam, and Olle Heimbürger),
co-workers at the research laboratory at PUC-PR (Andrea Stinghen, Aline
Hauser, Lia Nakao, Paulo Aveles, and Debora Grahl), and those at the
nephrology clinic involved in these studies (Miguel Riella, Paulo Fortes,
Thyago Moraes, Silvia Ribeiro, Simone Gonçalves, and Lucimary
Sylvestre).
Received 31 December 2008;
accepted 3 March 2009.
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TOP
ABSTRACT
STEP 1: BUILDING UP...
