THE JOHN F. MAHER AWARD RECIPIENT LECTURE 2008

Transcription

1 Peritoneal Dialysis International, Vol. 29, pp Printed in Canada. All rights reserved /09 $ Copyright 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 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? Perit Dial Int 2009; 29: Correspondence to: R. Pecoits Filho, Center for Health and Biological Sciences, Imaculada Conceição, 1155, Curitiba, PR Brazil. r.pecoits@pucpr.br Received 31 December 2008; accepted 3 March 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. 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 Cardiovascular disease represents the main cause of death in PD patients in most published studies, including 135

2 PECOITS FILHO MARCH 2009 VOL. 29, NO. 2 PDI 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) and IL 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 undera 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. STEP 2: SEARCHING FOR CONSISTENT BACKGROUND INFORMATION THAT MAY JUSTIFY THE HYPOTHESIS THAT INFLAMMATION PLAYS A CENTRAL ROLE IN CV COMPLICATIONS OF CKD 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. 136

3 PDI MARCH 2009 VOL. 29, NO. 2 INFLAMMATION IN PERITONEAL DIALYSIS stood. 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). STEP 3: REBUILDING THE RATIONALE WITH A FOCUS: THE IMPORTANCE OF INFLAMMATION IN CV COMPLICATIONS OF PD 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 stressinducing 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 137

4 PECOITS FILHO MARCH 2009 VOL. 29, NO. 2 PDI 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 138 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.

5 PDI MARCH 2009 VOL. 29, NO. 2 INFLAMMATION IN PERITONEAL DIALYSIS STEP 4: BACK TO THE PATIENT 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 thiolcontaining antioxidant) reduces composite CV end points in hemodialysis patients. The insulin-sensitizing thiazolidinediones, which are selective ligands of the nuclear transcription factor PPARγ, are the first drugs to address the basic problem of insulin resistance. PPARγ is expressed most abundantly in adipose tissue but is also found in pancreatic beta cells, vascular endothelium, and macrophages. Rosiglitazone is a PPARγ 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. SUMMARY AND CONCLUSIONS 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. DISCLOSURE 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. ACKNOWLEDGMENTS Studies cited in this manuscript were supported by funds obtained by the Division of Renal Medicine and Baxter Novum, 139

6 PECOITS FILHO MARCH 2009 VOL. 29, NO. 2 PDI 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. 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). REFERENCES 1. Fernandes N, Bastos MG, Cassi HV, Machado NL, Ribeiro JA, Martins G, et al. The Brazilian Peritoneal Dialysis Multicenter Study (BRAZPD): characterization of the cohort. Kidney Int Suppl 2008; 108:S Stenvinkel P, Pecoits-Filho R, Lindholm B. Coronary artery disease in end-stage renal disease: no longer a simple plumbing problem. J Am Soc Nephrol 2003; 14: Yao Q, Pecoits-Filho R, Lindholm B, Stenvinkel P. Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease. Scand J Urol Nephrol 2004; 38: Hauser AB, Stinghen AE, Kato S, Bucharles S, Aita C, Yuzawa Y, et al. Characteristics and causes of immune dysfunction related to uremia and dialysis. Perit Dial Int 2008; 28(Suppl 3):S Fortes PC, Versari PH, Stinghen AE, Pecoits-Filho R. Controlling inflammation in peritoneal dialysis: the role of PD-related factors as potential intervention targets. Perit Dial Int 2007; 27(Suppl 2):S Sylvestre LC, Fonseca KP, Stinghen AE, Pereira AM, Meneses RP, Pecoits-Filho R. The malnutrition and inflammation axis in pediatric patients with chronic kidney disease. Pediatr Nephrol 2007; 22: Pecoits-Filho R, Stenvinkel P, Heimburger O, Lindholm B. Beyond the membrane the role of new PD solutions in enhancing global biocompatibility. Kidney Int Suppl 2003; 88:S Stenvinkel P, Pecoits-Filho R, Lindholm B. Gene polymorphism association studies in dialysis: the nutrition 140

7 PDI MARCH 2009 VOL. 29, NO. 2 INFLAMMATION IN PERITONEAL DIALYSIS inflammation axis. Semin Dial 2005; 18: Pecoits-Filho R, Stenvinkel P, Marchlewska A, Heimburger O, Barany P, Hoff CM, et al. A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. Kidney Int Suppl 2003; 84:S Grahl DA, Axelsson J, Nordfors L, Heimburger O, Barany P, Qureshi AR, et al. Associations between the CYBA 242C/T and the MPO -463G/A polymorphisms, oxidative stress and cardiovascular disease in chronic kidney disease patients. Blood Purif 2007; 25: Honda H, Qureshi AR, Heimburger O, Barany P, Wang K, Pecoits-Filho R, et al. Serum albumin, C-reactive protein, interleukin 6, and fetuin A as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis 2006; 47: Nascimento MM, Pecoits-Filho R, Qureshi AR, Hayashi SY, Manfro RC, Pachaly MA, et al. The prognostic impact of fluctuating levels of C-reactive protein in Brazilian haemodialysis patients: a prospective study. Nephrol Dial Transplant 2004; 19: Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, et al. Aspects of immune dysfunction in endstage renal disease. Clin J Am Soc Nephrol 2008; 3: Pecoits-Filho R, Stenvinkel P, Wang AY, Heimburger O, Lindholm B. Chronic inflammation in peritoneal dialysis: the search for the holy grail? Perit Dial Int 2004; 24: Pecoits-Filho R, Araujo MR, Lindholm B, Stenvinkel P, Abensur H, Romao JE Jr, et al. Plasma and dialysate IL-6 and VEGF concentrations are associated with high peritoneal solute transport rate. Nephrol Dial Transplant 2002; 17: Pecoits-Filho R, Carvalho MJ, Stenvinkel P, Lindholm B, Heimburger O. Systemic and intraperitoneal interleukin-6 system during the first year of peritoneal dialysis. Perit Dial Int 2006; 26: Pecoits-Filho R. The peritoneal cavity: a room with a view to the endothelium. Perit Dial Int 2005; 25: Pecoits-Filho R, Lindholm B, Axelsson J, Stenvinkel P. Update on interleukin-6 and its role in chronic renal failure. Nephrol Dial Transplant 2003; 18: Pecoits-Filho R, Barany P, Lindholm B, Heimburger O, Stenvinkel P. Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol Dial Transplant 2002; 17: Cooker LA, Luneburg P, Holmes CJ, Jones S, Topley N; for the Bicarbonate/Lactate Study Group. Interleukin-6 levels decrease in effluent from patients dialyzed with bicarbonate/lactate-based peritoneal dialysis solutions. Perit Dial Int 2001; 21(Suppl 3):S Pecoits-Filho R, Goncalves S, Barberato SH, Bignelli A, Lindholm B, Riella MC, et al. Impact of residual renal function on volume status in chronic renal failure. Blood Purif 2004; 22: Goncalves S, Pecoits-Filho R, Perreto S, Barberato SH, Stinghen AE, Lima EG, et al. Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol Dial Transplant 2006; 21: Fortes PCN, Mendes JG, Riella MC, Pecoits-Filho RF. Carbohydrate metabolism disturbances in nondiabetic patients on peritoneal dialysis [Abstract]. Perit Dial Int 2006; 26(Suppl 2):S Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: Wong TY, Szeto CC, Chow KM, Chan JC, Li PK. Prognostic role of serum ACE activity on outcome of type 2 diabetic patients on chronic ambulatory peritoneal dialysis. Am J Kidney Dis 2002; 39: Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000; 356(9237): Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Circulation 2003; 107: Wong TY, Szeto CC, Chow KM, Leung CB, Lam CW, Li PK. Rosiglitazone reduces insulin requirement and C-reactive protein levels in type 2 diabetic patients receiving peritoneal dialysis. Am J Kidney Dis 2005; 46: