Roberto Pecoits-Filho

Aspects of Immune Dysfunction in End-stage Renal Disease

End-stage renal disease (ESRD) is associated with significantly increased morbidity and mortality resulting from cardiovascular disease (CVD) and infections, accounting for 50% and 20%, respectively, of the total mortality in ESRD patients. It is possible that these two complications are linked to alterations in the immune system in ESRD, as uremia is associated with a state of immune dysfunction characterized by immunodepression that contributes to the high prevalence of infections among these patients, as well as by immunoactivation resulting in inflammation that may contribute to CVD. This review describes disorders of the innate and adaptive immune systems in ESRD, underlining the specific role of ESRD-associated disturbances of Toll-like receptors. Finally, based on the emerging links between the alterations of immune system, CVD, and infections in ESRD patients, it emphasizes the potential role of the immune dysfunction in ESRD as an underlying cause for the high mortality in this patient population and the need for more studies in this area.

Associations between circulating inflammatory markers and residual renal function in CRF patients

BACKGROUND Circulating levels of cytokines and other inflammation markers are markedly elevated in patients with chronic renal failure. This could be caused by increased generation, decreased removal, or both. However, it is not well established to what extent renal function per se contributes to the uremic proinflammatory milieu. The aim of the present study is to analyze the relationship between inflammation and glomerular filtration rate (GFR) in 176 patients (age, 52 +/- 1 years; GFR, 6.5 +/- 0.1 mL/min) close to the initiation of renal replacement therapy. METHODS Circulating levels of high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), hyaluronan, and neopterin were measured after an overnight fast. Patients subsequently were subdivided into two groups according to median GFR (6.5 mL/min). RESULTS Despite the narrow range of GFR (1.8 to 16.5 mL/min), hsCRP, hyaluronan, and neopterin levels were significantly greater in the subgroup with lower GFRs, and significant negative correlations were noted between GFR and IL-6 (rho = -0.18; P < 0.05), hyaluronan (rho = -0.25; P < 0.001), and neopterin (rho = -0.32; P < 0.0005). In multivariate analysis, although age and GFR were associated with inflammation, cardiovascular disease and diabetes mellitus were not. CONCLUSION These results show that a low GFR per se is associated with an inflammatory state, suggesting impaired renal elimination of proinflammatory cytokines, increased generation of cytokines in uremia, or an adverse effect of inflammation on renal function.

Coronary Artery Disease in End-Stage Renal Disease: No Longer a Simple Plumbing Problem

The lifespan of patients with end-stage renal disease (ESRD) is reduced, and cardiovascular disease (CVD) accounts for a premature death in more than 50% of patients from Western Europe and North America undergoing regular dialysis ([1][1]). Actually, the risk for CVD in a 30-yr-old ESRD patient is

Left Ventricular Mass in Chronic Kidney Disease and ESRD

Chronic kidney disease (CKD) and ESRD, treated with conventional hemo- or peritoneal dialysis are both associated with a high prevalence of an increase in left ventricular mass (left ventricular hypertrophy [LVH]), intermyocardial cell fibrosis, and capillary loss. Cardiac magnetic resonance imaging is the best way to detect and quantify these abnormalities, but M-Mode and 2-D echocardiography can also be used if one recognizes their pitfalls. The mechanisms underlying these abnormalities in CKD and ESRD are diverse but involve afterload (arterial pressure and compliance), preload (intravascular volume and anemia), and a wide variety of afterload/preload independent factors. The hemodynamic, metabolic, cellular, and molecular mediators of myocardial hypertrophy, fibrosis, apoptosis, and capillary degeneration are increasingly well understood. These abnormalities predispose to sudden cardiac death, most likely by promotion of electrical instability and re-entry arrhythmias and congestive heart failure. Current treatment modalities for CKD and ESRD, including thrice weekly conventional hemodialysis and peritoneal dialysis and metabolic and anemia management regimens, do not adequately prevent or correct these abnormalities. A new paradigm of therapy for CKD and ESRD that places prevention and reversal of LVH and cardiac fibrosis as a high priority is needed. This will require novel approaches to management and controlled interventional trials to provide evidence to fuel the transition from old to new treatment strategies. In the meantime, key management principles designed to ameliorate LVH and its complications should become a routine part of the care of the patients with CKD and ESRD.

Plasma Pentosidine Is Associated with Inflammation and Malnutrition in End-Stage Renal Disease Patients Starting on Dialysis Therapy

Pentosidine is an advanced glycation end-product (AGE), formed by glycosylation and oxidation, that accumulates markedly in end-stage renal disease (ESRD). It has been speculated that AGE and carbonyl stress contributes to long-term complications such as cardiovascular disease (CVD) in ESRD patients. This study determined plasma levels of pentosidine as well as the presence of inflammation (CRP > or = 10 mg/L), clinical CVD (CVD(clin)), and malnutrition (subjective global assessment [SGA] > 1) in a cohort of 191 ESRD patients, median age of 55 yr (range, 23 to 70 yr) and median GFR = 7 ml/min (range, 2 to 17 ml/min), close to start of renal replacement therapy. Fifty-one elderly subjects, median age of 82 yr (range, 71 to 110 yr), with mild renal impairment, median GFR = 67 ml/min (range, 38 to 113 ml/min), were also studied for comparative analysis of plasma pentosidine. The plasma pentosidine content was elevated in all patients compared with the levels in the elderly subjects and were negatively correlated with GFR both in the ESRD patients (Rho = -0.24; P < 0.01; n = 159) and in the elderly subjects (Rho = -0.31; P < 0.05). Moreover, the plasma pentosidine content was correlated with age in the ESRD patients (Rho = 0.26; P < 0.001) and in the elderly subjects (Rho = 0.44; P < 0.001). The 63 malnourished ESRD patients (35%) had a significantly higher (P < 0.05) median plasma pentosidine than the well-nourished patients (39 versus 27 pmol/mg albumin). Similarly, 73 inflamed patients (38%) had a significantly higher (P < 0.001) median pentosidine content compared with 118 non-inflamed patients (37 versus 24 pmol/mg albumin). Also, the plasma pentosidine content showed weak but significant positive correlations with CRP (Rho = 0.28; P < 0.0001), fibrinogen (Rho = 0.23; P < 0.01; n = 126), IL-6 (Rho = 0.22; P < 0.01; n = 169), and soluble vascular cellular adhesion molecule-1 (Rho = 0.38; P < 0.001; n = 74). On the other hand, no significant differences in plasma pentosidine content were noted between the patients with and those without CVD(clin) (32 versus 27 pmol/mg albumin, respectively). Analyses of all-cause mortality, by Kaplan-Meier, showed that mortality was not linked to the plasma pentosidine content. Moreover, survival analysis by the Cox regression model showed that age (P < 0.001), diabetes mellitus (P < 0.01), malnutrition (P < 0.01), and CVD(clin) (P < 0.01) independently predicted poor outcome, whereas an elevated plasma pentosidine content did not. The present study shows that an elevated plasma pentosidine content in ESRD patients is significantly associated with both inflammation and malnutrition and confirms that low residual renal function and high age further contribute to an increased plasma pentosidine content. However, in this small cohort, the plasma pentosidine content did not predict outcome. Thus, accumulation of plasma pentosidine is unlikely to be an appropriate clinically useful marker to predict mortality in ESRD patients.

Traditional and non-traditional risk factors as contributors to atherosclerotic cardiovascular disease in end-stage renal disease

Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in patients with end-stage renal disease (ESRD). Although traditional risk factors, such as diabetes mellitus, hypertension, dyslipidemia and advanced age, are prevalent in ESRD patients they may not be sufficient by themselves to account for the high prevalence of CVD in patients with this condition. Thus, the search for other, non-traditional, risk factors that may be involved in the pathogenesis of uremic CVD has been an area of intense study. Data suggest that the accelerated atherosclerotic process of ESRD may involve several interrelated processes, such as oxidative stress, endothelial dysfunction and vascular calcification, in a milieu of constant low-grade inflammation. The cause(s) of inflammation in ESRD are multifactorial and, while it may reflect underlying CVD, an acute-phase reaction may also be a direct cause of vascular injury via several pathogenetic mechanisms. Available data suggest that pro-inflammatory cytokines play a central role in the genesis of both malnutrition and CVD in ESRD. Thus, it could be speculated that suppression of the vicious cycle of malnutrition, inflammation and atherosclerosis (MIA syndrome) would improve survival in dialysis patients. Recent evidence has demonstrated strong associations between inflammation and both increased oxidative stress and endothelial dysfunction in ESRD patients. As there is not yet any recognized, or even proposed, treatment for ESRD patients with chronic inflammation it would be of obvious interest to study the long-term effect of various anti-inflammatory treatment strategies on the nutritional and cardiovascular status as well as outcome of these patients.

Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy

The global nephrology community recognises the need for a cohesive plan to address the problem of chronic kidney disease (CKD). In July, 2016, the International Society of Nephrology hosted a CKD summit of more than 85 people with diverse expertise and professional backgrounds from around the globe. The purpose was to identify and prioritise key activities for the next 5-10 years in the domains of clinical care, research, and advocacy and to create an action plan and performance framework based on ten themes: strengthen CKD surveillance; tackle major risk factors for CKD; reduce acute kidney injury-a special risk factor for CKD; enhance understanding of the genetic causes of CKD; establish better diagnostic methods in CKD; improve understanding of the natural course of CKD; assess and implement established treatment options in patients with CKD; improve management of symptoms and complications of CKD; develop novel therapeutic interventions to slow CKD progression and reduce CKD complications; and increase the quantity and quality of clinical trials in CKD. Each group produced a prioritised list of goals, activities, and a set of key deliverable objectives for each of the themes. The intended users of this action plan are clinicians, patients, scientists, industry partners, governments, and advocacy organisations. Implementation of this integrated comprehensive plan will benefit people who are at risk for or affected by CKD worldwide.

Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

Soluble leptin receptors and serum leptin in end-stage renal disease: relationship with inflammation and body composition

Background Elevated serum leptin (S‐leptin) levels have been reported in patients with end‐stage renal disease (ESRD). Apart from the decreased glomerular filtration rate (GFR), body composition and inflammation may affect leptin levels in ESRD. Leptin circulates both free of and bound to soluble leptin receptors (sOB‐R), which are the main determinants of leptin activity and have not been described in ESRD until now.

Inflammation contributes to low plasma amino acid concentrations in patients with chronic kidney disease

BACKGROUND Inflammation and malnutrition are common in chronic kidney disease (CKD) patients, and plasma concentrations of free amino acids (AAs) in these patients are often abnormal. Malnutrition contributes to alterations in AA concentrations. OBJECTIVE The objective was to study the effects of inflammation on plasma AA concentrations. DESIGN Concentrations of plasma AAs, serum albumin, and several inflammatory markers were analyzed in 200 fasting, nondiabetic CKD patients who were close to the start of renal replacement therapy. The nutritional status of these patients was assessed by a subjective global assessment. RESULTS The patients with inflammation [C-reactive protein (CRP) concentrations >10 mg/L] or malnutrition had lower AA concentrations than did the patients with no inflammation or malnutrition. The presence of both inflammation and malnutrition was associated with more marked reductions in AA concentrations than was malnutrition alone. Significant inverse correlations were observed between the plasma concentrations of most of the essential and nonessential AAs and inflammatory markers, whereas serum albumin concentrations were positively correlated with several AA concentrations. A stepwise multivariate regression analysis showed that serum CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs. An analysis of all-cause mortality with a Kaplan-Meier test showed that the patients with higher AA concentrations had significantly better survival than did the patients with lower AA concentrations. CONCLUSIONS Plasma AA concentrations are low in CKD patients with inflammation and are inversely correlated with concentrations of inflammatory markers. Although inflammation and malnutrition are closely related, CRP concentrations were independently associated with low concentrations of the sums of both nonessential AAs and all AAs, which suggests an independent role of inflammation as a cause of low plasma AA concentrations in CKD patients.