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Inflammation and Fibrosis |
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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Cardiovascular (CV) disease is the main cause of death in peritoneal
dialysis (PD) patients, but the mechanisms mediating the increased CV risk
observed in this group of patients are still largely unknown, which limits the
perspective on effective therapeutic strategies. Patients on PD are already
exposed to a number of traditional risk factors from the start of their
chronic kidney disease (CKD), because many of those risk factors are common to
CV disease and CKD alike. As renal dysfunction progresses, CKD-related risk
factors are introduced, changing the profile of both the CV disease and the
markers of risk. In this phase, which usually starts when glomerular
filtration rate falls below 60 mL/min, the list of risk factors is expanded to
include disturbances of mineral metabolism, anemia, fluid overload, uremic
toxicity, and increased signs of oxidative stress and inflammation. Although
many of the risk factors linked to CV burden are not related to the dialytic
procedure, additional harm is introduced after the initiation of
PD—with, for example, the presence of chronic infections and factors
related to PD fluids, particularly reabsorption of glucose. In the present
article, we review the impact of the novel risk factors introduced with the
initiation of PD therapy, and we propose potential therapeutic strategies
(which remain to be tested) for reducing CV mortality in this group of
patients.
KEY WORDS: Cardiovascular disease; risk factors; glucose absorption.
Cardiovascular (CV) disease is the main cause of death in peritoneal dialysis (PD) patients, but the mechanisms mediating the increased CV risk observed in this group of patients are still largely unknown, which limits the perspective on effective therapeutic strategies (1). The leading hypothesis that tries to explain the high CV risk observed in PD patients is the exposure that already exists for those patients to a number of traditional risk factors at the start of their chronic kidney disease (CKD). Many of those risk factors are common to CV disease and CKD alike.
As renal dysfunction progresses, CKD-related risk factors are introduced, changing the profile of both the CV disease and the markers of risk. In this phase, which usually starts when glomerular filtration rate (GFR) falls below 60 mL/min, the list of risk factors is expanded to include disturbances of mineral metabolism, anemia, fluid overload, uremic toxicity, and increased signs of oxidative stress and inflammation. Although many of the risk factors linked to CV burden are not related to the dialytic procedure, additional harm is introduced after the initiation of PD—with, for example, the presence of chronic infections and factors related to PD fluids, particularly reabsorption of glucose (1). In the present article, we review the impact of PD initiation, with its introduction of novel risk factors related to the therapy, and we define potential therapeutic strategies (which remain to be tested) for reducing CV mortality in this group of patients.
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DISCUSSION |
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The vascular endothelium, once considered a barrier between intravascular and interstitial compartments, is nowadays considered much more than an inert, singlecell lining that covers the internal surface of blood vessels. In normal conditions, the endothelium actively reduces 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. Interestingly, peritoneal vascular permeability can also be affected by risk factors for CV disease. Indeed, the Peritoneal Biopsy Registry shows that patients with CKD present peritoneal membrane alterations concomitant with functional changes typically characterized by a high small-solute (and perhaps also large-solute) transport rate even before the initiation of PD. For reasons yet to be fully understood, fast transporters have increased mortality on PD (5,6).
Recently, Szeto et al. showed that peritoneal albumin excretion (which is conceptually analogous to microalbuminuria in non-uremic patients) can predict CV disease in PD patients (7). It is important to note that all studies defining the high risk of mortality in patients with a high peritoneal solute transport rate analyzed only the transport of small solutes and never described a correlation between the transport rates of small and large solutes. High intrinsic permeability of the peritoneum (and consequently high peritoneal protein excretion) may be a direct reflection of endothelial dysfunction, and peritoneal transport of macromolecules may therefore be an interesting way of measuring the degree of CV risk.
Several factors induce vascular damage, which leads to a change in endothelial cell phenotype characterized by impaired nitric oxide production, altered smoothmuscle cell relaxation and proliferation, reduced angiogenesis, activation of coagulation, and increased cell adhesion to the vascular wall (8). Atherosclerotic CV disease is initiated and perpetuated by the interaction of immune cells with cells of the vessel wall, mediated by chemokines and adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 (MCP-1) (9).
Evidence generated from experimental and clinical studies is increasingly suggesting that these early stages of atherosclerosis are extremely important (10). In addition, prospective data strongly imply that endothelial-activated oxidative stress and inflammation occur early in the atherosclerotic process and that high serum levels of chemokines and adhesion molecules are predictors of future CV events in the general (11) and CKD (12) populations. Also notable are the strong associations between surrogate markers of inflammation and plasma levels of adhesion molecules (11). From a clinical viewpoint, high circulating levels of MCP-1 are observed in patients with acute myocardial infarction and unstable angina (13), and are associated with inflammation, dyslipidemia, and CV events in hemodialysis (HD) patients (14).
Since the first report by Bergström and co-workers (14) of an association between elevated C-reactive protein (CRP) and increased mortality, several groups have reported almost identical findings in other series (and using other markers of inflammation), including patients on PD (15–17). Although the association between single or multiple measures of inflammation markers and an increase risk of mortality among 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 damage to target organs or whether it represents an epiphenomenon is still an unanswered question. Because efficient therapeutic strategies may have to be directed toward reducing the causative factors of the inflammatory response, a more in-depth analysis of the factors associated with inflammation and oxidative stress is absolutely necessary if targets for intervention are to be defined.
Many factors that are present even before the initiation of PD can be considered potential triggers of the inflammatory response. Uremic toxicity, accumulation of modified proteins (such as advanced glycation end-products), retention of cytokines, mechanical stress on the vascular wall as a result of hypertension, comorbidities such as advanced age and diabetes, and extraosseous calcification are just a few examples of factors unrelated to dialysis treatment that could potentially trigger the inflammatory response. Upon introduction of PD, other inflammation and oxidative stress–inducing factors are added to that list. These potential additional causes that have to be considered include chronic infections related to PD, absorption of glucose degradation products present in the dialysate, transient intraperitoneal acidosis, and intraperitoneal inflammation and oxidative stress (with potential impact on the systemic side). Finally, the presence of glucose as the osmotic agent in PD fluid is also a potential villain, inducing systemic complications. In the subsection that follows, we review how the consequences of glucose absorption can be linked to inflammation and oxidative stress, and how reducing glucose use can be an important strategy for reducing CV risk in PD patients.
DISTURBANCES OF CARBOHYDRATE METABOLISM: A LINK BETWEEN PD, INFLAMMATION, AND CV RISK
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 manifested as abnormal glycemic
responses during oral and intravenous glucose tolerance tests, although most
patients can maintain normoglycemia at the expense of hyperinsulinemia
(18). This altered metabolism
is associated both with an unexplained impaired insulin sensitivity and with
complex disruptions in the temporal pattern of insulin release, differing both
from that of healthy individuals and from that observed in other states of
insulin resistance (19).
Insulin resistance, defined mainly as a markedly decreased sensitivity in peripheral tissue, appears early in the course of renal disease, even when GFR values are still within the normal range (20). The effect of intravenous insulin on hepatic glucose production and splanchnic glucose uptake are not altered by uremia (21). The insulin resistance index by homeostasis model assessment (HOMA) closely mirrors insulin resistance by the standard glucose clamp (22). In fact, HOMA can be used as an alternative method of assessing insulin resistance in patients with CKD (23), and insulin resistance is an independent factor involved in CV risk in those patients (24).
Particularly in PD patients using glucose-based solutions (in whom glucose is partly absorbed from the peritoneal cavity to the circulation), systemic glucose load may have an impact on the metabolic disorders described above. Indeed, concern about the adverse systemic effects of absorbed glucose is increasing, particularly with regard to CV risk profile (25).
Interestingly, we recently described a state of insulin resistance, mild increase in fasting glycemia, dyslipidemia, and altered glycated hemoglobin (HbA1c) in a group of nondiabetic PD patients—a state that was markedly worse in PD patients than in those on HD (26). These preliminary data point to a complex metabolic disorder of carbohydrate metabolism present in PD patients, with potential effects on the CV system.
The mechanism by which the altered carbohydrate metabolism may lead to an increase in CV risk is just now being understood, but emerging evidence points to an important role of the central obesity–insulin resistance–inflammation axis. Several studies have demonstrated that increases in calorie and fat dietary intake lead to the development of central obesity, and that central fat tissue is immunologically active: that is, it is able to attract macrophages and initiate production of inflammatory mediators that ultimately lead to insulin resistance, hepatic steatosis, and accelerated atherogenesis (27).
Accordingly, in a large cohort of dialysis patients, we observed that high plasma levels of MCP-1 (a central mediator of the early atherogenic response) were significantly associated with hypertension, abdominal circumference, HOMA index, and fasting glucose (28).
During PD performed with glucose-based solutions, constant absorption of glucose from the dialysate is associated with a potential worsening of the aforementioned disorders of carbohydrate metabolism. With the addition of hypertension, dyslipidemia, and central obesity (which are all common features of PD patients), metabolic syndrome (MetS, a cluster of risk factors related to increased morbidity and mortality in the general population) potentially develops in a high proportion of these patients.
In a recent cross-sectional study, we observed that 53% of our PD patients met the criteria for MetS, a significantly higher percentage than was observed in HD patients (28).
In the general population, MetS has been associated with hepatic steatosis and increased signs of biomarkers of inflammation, and leads to an increased risk for CV disease (29). Although the impact of MetS on clinical outcome in PD dialysis patients has not yet been described, a few studies have noted the relationship between abnormal fasting glycemia (30) and HbA1c (31) and increased mortality in groups of nondiabetic patients. Also, in the Third National Health and Nutrition Examination Survey, an association was observed between MetS and inflammation at varying levels of renal function (32). A recent prospective study involving renal patients evaluated insulin resistance and CV events and concluded that several components of MetS are associated with CV events (33).
Based on the foregoing observations, we hypothesize that the continuous absorption of glucose during PD leads to a progressive increase in central fat accumulation, inducing a worsening of insulin resistance, hepatic steatosis, and endothelial dysfunction, and resulting in an increase in the concentration of plasma adhesion molecules, chemokines, and surrogate markers of inflammation. Those inflammatory mediators orchestrate the organ damage in the vascular wall and in other target organs.
COMPONENTS OF MetS IN PD: CENTRAL OBESITY, DYSLIPIDEMIA, AND INSULIN RESISTANCE
Unlike studies of HD patients, which consistently show a short-term
survival advantage for obesity, studies looking at the effect of obesity on
survival in PD patients present conflicting results. Although some studies
suggest that obesity is a risk factor for mortality in PD patients
(34), long-term PD survivors
are not obese (35).
Alterations in body composition that are not detected when obesity is defined
according to body mass index may explain some of those paradoxical
findings.
A recent study that used 24-hour urinary creatinine as an indirect marker of muscle mass showed that high-BMI patients with low muscle mass had a higher risk of all-cause and CV death (36). Studies looking at fat mass (particularly the visceral kind) as a determinant of higher mortality risk would most likely produce results that are more consistent.
One potential adverse effect of obesity on the survival of PD patients is
its association with chronic inflammatory syndrome. One small cross-sectional
study found elevated blood levels of tumor necrosis factor 
(TNF-), CRP, and leptin in obese PD patients
(37). Further studies will
need to clarify whether strategies aimed at reducing fat mass will reduce
inflammation and mortality in PD patients.
Dyslipidemia is highly prevalent in dialysis patients, and the concomitant occurrence of several risk factors in a given patient is observed more often in PD patients than in HD patients (38). Hypertriglyceridemia is the most common dyslipidemia in PD patients. The prevalence of hypertriglyceridemia during the first year of PD treatment has been reported to be as high as 70% (38). In addition, a recent study showed that patients with high triglyceride levels were more insulin-resistant than those with normal triglyceride levels (39).
Many factors are implicated in the development of insulin resistance in uremic patients. The adipokines and cytokines secreted by adipose tissue have direct effects and play a central role in this process (40), but until recently, only a few studies had investigated the impact of adipokines on the metabolic and inflammatory aspects of CKD. Anemia, metabolic acidosis, and secondary hyperparathyroidism can also increase insulin resistance by indirect mechanisms (41). Although insulin resistance improves after 5 weeks on HD (42), the long-term effects of PD on insulin resistance are unknown at the moment.
THERAPEUTIC PERSPECTIVES
The insulin-sensitizing thiazolidinediones, which are selective ligands of
the nuclear transcription factor peroxisome proliferator–activated
receptor 
(PPARG), are the first drugs to address the basic problem of
insulin resistance. Expression of PPARG is most abundant in adipose
tissue, but also occurs in pancreatic beta cells, vascular endothelium, and
macrophages (43).
Rosiglitazone is a PPARG agonist that has anti-inflammatory properties and
that has been tried with PD patients with type 2 diabetes. A significantly
greater reduction in insulin dosage was observed in the treatment group than
in the control group. At the end of the study, patients treated with
rosiglitazone also had significantly lower CRP levels than did patients in the
control group (44). In another
study, rosiglitazone also improved insulin resistance in PD patients without
diabetes (45). Pioglitazone
was tested against glipizide in a randomized, 16-week trial that set out to
assess the effects of these agents on markers of oxidative stress and
inflammation in patients with diabetes. Pioglitazone reduced CRP by 41%,
interleukin-6 by 38%, and matrix metalloproteinase-9 by 29%. No statistically
significant changes in TNF- concentrations or in levels of oxidative
stress markers were observed with either hypoglycemic agent
(46). Whether long-term use of
thiazolidinediones reduces CV risk requires further study.
Finally, the impact of low-glucose regimens and of alternative solutions that use other osmotic agents will need to be further analyzed in clinical studies, because currently, no study definitively shows a benefit for nonglucose peritoneal fluids over glucose-based fluids. However, a few studies point to metabolic benefits for icodextrin that are potentially linked to reduced inflammation and CV disease. Icodextrin has been shown to reduce insulin resistance (47) and hypertriglyceridemia (48), to promote better ultrafiltration (49–51), and to preserve membrane function (52) in PD patients. Interestingly, a retrospective study showed a reduction in mortality and patient drop-out associated with icodextrin use (53). Reduction of glucose load will likely be an important strategy to reduce CV mortality in patients on PD.
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CONCLUSIONS |
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This article has been cited by other articles:
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  R. Pecoits-Filho APPLYING TRANSLATIONAL RESEARCH IN UNDERSTANDING COMPLICATIONS AND DEFINING TARGETS FOR INTERVENTION: INFLAMMATION IN PD AS A MODEL Perit. Dial. Int., March 1, 2009; 29(2): 135 - 141. [Abstract] [Full Text] [PDF]
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