Simone Gonçalves

Increased plasma and endothelial cell expression of chemokines and adhesion molecules in chronic kidney disease.

Chemokines and adhesion molecules are involved in early events of atherogenesis. In the present study, we investigated the effects of the uremic milieu on the expression of monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) and their relationship to cardiovascular status. Plasma samples were obtained from patients in different stages of chronic kidney disease (CKD). Cardiovascular status was evaluated by intima-media thickness and endothelial dysfunction by flow mediation dilatation and proteinuria. In vitro studies were performed using human umbilical endothelial cells exposed to uremic plasma or plasma from healthy subjects. MCP-1, IL-8, sVCAM-1 and sICAM-1 levels in plasma and in supernatant were analyzed by enzyme-linked immunosorbent assay. The population consisted of 73 (mean age 57 years; 48% males) CKD patients with glomerular filtration rate (GFR) of 37 ± 2 ml/min. MCP-1 and sVCAM-1 plasma levels were negatively correlated with GFR (ρ = –0.40, p < 0.0005 and ρ = –0.42, p < 0.0005, respectively). Fibrinogen was positively correlated with MCP-1, sICAM-1 and sVCAM-1 (ρ = 0.33, p < 0.005, ρ = 0.32, p < 0.05 and ρ = 0.25, p < 0.05, respectively) and ultra-high-sensitivity C-reactive protein was positively correlated with sICAM-1 (ρ = 0.25, p < 0.0005). Plasma IL-8 had a significant positive correlation with proteinuria (ρ = 0.31, p < 0.01). There was a time- and CKD-stage-dependent MCP-1, IL-8 and sVCAM-1 endothelial expression (p < 0.05). In summary, plasma levels of markers of endothelial cell activation (MCP-1 and sVCAM-1) are increased in more advanced CKD. Exposure of endothelial cells to uremic plasma results in a time- and CKD-stage-dependent increased expression of MCP-1, IL-8 and sVCAM-1, suggesting a link between vascular activation, systemic inflammation and uremic toxicity. Future studies are necessary to investigate whether these biomarkers add predictive value in comparison to the previously described ones. Also, endothelial response to uremic toxicity should be viewed as a potential target for intervention in order to reduce morbidity and mortality in CKD-related cardiovascular disease.

Impact of Residual Renal Function on Volume Status in Chronic Renal Failure

During the past few years, it has become increasingly evident that residual renal function (RRF) is an important and independent predictor of poor outcome in patients with chronic kidney disease (CKD). Although the causes of this observation are not fully understood, it appears that the loss of RRF impairs both fluid removal and clearance of solutes, which in turn leads to uremic toxicity and increased morbidity and mortality. There is increasing evidence that patients with CKD develop signs of fluid overload already in the early phases of the disease, and this may be a stimulus for inflammatory activation. Recently, an inflammatory component was identified in uremic atherosclerotic and non-atherosclerotic cardiovascular disease (CVD), which have been consistently associated with poor clinical outcome in patients with CKD. Signs of systemic inflammation occur in parallel to the impairment in renal function, and the pathophysiology is most likely multifactorial, including a decrease in cytokine clearance, advanced glycation end-product accumulation, oxidative stress, and principal fluid overload. Additionally, inflammation seems to be a predictor of accelerated loss of renal function. In this article, we discuss the evidence showing that patients with CKD generally have fluid overload, the mechanisms by which impaired renal function may lead to a chronic inflammatory state, and the available information linking fluid overload to accelerated loss of renal function and CVD through inflammation. Inflammation may lead to the development of complications of CKD, in particular CVD, but on the other hand may also lead to a faster progression of renal disease. Strategies aiming to reduce fluid overload may be useful to reduce cardiovascular morbidity and mortality, but also preserve RRF.

Sevelamer decreases systemic inflammation in parallel to a reduction in endotoxemia.

Introduction: Uremic toxins play a pivotal role in the development of systemic complications of chronic kidney disease (CKD), which are largely mediated by the activation of the immune system. Triggers of inflammation in CKD are largely unknown and strategies aiming to reduce circulating ligands that could start the inflammatory response are potentially important. In the present study, we investigated the impact of sevelamer hydrochloride treatment in reducing endotoxemia and inflammation in a group of hemodialysis (HD) patients. Material and Methods: HD patients, who were converted from calcium carbonate treatment to sevelamer according to KDOQI guidelines, were included and prospectively followed for 6 months. Systemic inflammation was evaluated by serum ultra-high-sensitivity C-reactive protein (hsCRP) using an automated immunoturbidimetric assay. Endotoxin was measured using Limulus amebocyte lysate chromogenic endpoint assay. All the analyses were performed immediately before conversion and after 6 months of treatment. Results: After the exclusion of patients discontinuing the treatment, 20 patients (mean dialysis time 12 ± 4 months on HD, age 52 ± 2 years, 38% males, 11% diabetics) were included in the analysis. No significant changes were observed in Ca, P and PTH levels, while a reduction in cholesterol levels was seen. Plasma concentration of hsCRP and endotoxin significantly decreased after 6 months of conversion to sevelamer compared with baseline. Conclusion: We conclude that sevelamer treatment leads to a decrease in hsCRP levels, which was accompanied by a parallel decrease in endotoxemia, suggesting that endotoxemia may contribute to the systemic inflammation in HD patients, which was partially reduced by the use of sevelamer.

A gut feeling on endotoxemia: causes and consequences in chronic kidney disease.

Chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular calcification, accelerated atherosclerosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. As a consequence, inflammation is a predictor of mortality in this group of patients. Specific causes of the activation of the immune system in CKD are largely unknown. Endotoxin (ET) release to the circulation represents a potentially important target for interventions aiming to reduce mortality in CKD patients. In this minireview, we propose that there are several potential sources of endotoxemia in CKD and that gut translocation, leading to the generation of ligands of the innate immune response, represents a potentially reversible cause. Prevention of endotoxemia, through treating foci of ET (periodontal disease, catheters, vascular access) or reducing translocation from the gut, will potentially reduce the inflammatory response.

Association between Biomarkers of Carbonyl Stress with Increased Systemic Inflammatory Response in Different Stages of Chronic Kidney Disease and after Renal Transplantation

Background: Chronic kidney disease (CKD) is characterized by progressive kidney dysfunction accompanied by accumulation of uremic toxins and a potential disequilibrium between the redox status and the generation of prooxidants, resulting in oxidative stress and chronic inflammation which is associated with complications (particularly cardiovascular disease) in this population. We aimed to analyze the concentration of total plasma thiols (indicator of antioxidant capacity) and the protein carbonyl content (a marker of carbonyl stress) in relation to kidney function and inflammation in a group of patients with CKD. Patients and Methods: A group of 68 patients with CKD (stages 2–5; mean age 57 ± 12 years, 46% male, 34% diabetics) and another group of 21 patients who underwent living donor kidney transplantation (mean age 36 ± 17 years, 50% male, 10% diabetics, and 9 ± 2 months after renal transplantation) were included in the study. Total plasma thiol and protein carbonyl levels were determined by the DTNB and DNPH methods, respectively, and were adjusted to the plasma albumin concentrations. Plasma levels of fibrinogen and C-reactive protein (CRP) were measured by routine methods and used as markers of inflammation. Results: Mean glomerular filtration rate (GFR) was 48 ml/min, and there was a positive correlation between GFR and thiol (r = 0.25, p < 0.05) and a negative correlation between GFR and carbonyl (r = –0.26, p < 0.05), fibrinogen (r = –0.45, p < 0.0001) and CRP (r = –0.14, p = ns). Carbonyl strongly correlated with CRP (0.49, p < 0.0001) and fibrinogen (0.30, p < 0.01). There was a significant reduction in plasma carbonyl after renal transplantation (1.4 ± 0.4 nmol/mg albumin), compared with the levels before the procedure (2.0 ± 1.4 nmol/mg albumin, p < 0.05), which parallels an improvement in thiol levels (15 ± 4 vs. 21 ± 5 nmol/mg albumin, p < 0.001). In addition, there was a significant correlation between CRP and carbonyl after the transplantation (r = 0.65; p < 0.005). Conclusion: We observed that patients with CKD present an altered redox status and increased signs of carbonyl stress and inflammatory activity as kidney function deteriorates, which was partially but significantly improved after renal transplantation. These findings indicate the importance of renal function in the complications of CKD related to oxidative stress and inflammation.

Sevelamer Carbonate Reduces Inflammation and Endotoxemia in an Animal Model of Uremia

Background: Renal failure is associated with activation of inflammatory response, but the mechanisms behind this observation and potential anti-inflammatory strategies are yet to be defined. Endotoxin (ET) translocation from the intestinal lumen can potentially trigger systemic inflammatory response, and ET binding represents a potential anti-inflammatory strategy in renal failure. The aim of this study was to evaluate the ET-binding capacity of sevelamer carbonate in an animal model of renal failure. Material and Methods: Rats were 5/6 nephrectomized to induce uremia (U) and sham-operated rats were allocated to receive normal chow (controls) or a diet with 3% sevelamer carbonate added (+SC) for 60 days. Tumor necrosis factor-α (TNF-α) and ET were measured in plasma on days 7, 30 and 60 in all animals. Results: Renal failure induced an inflammatory response, since TNF-α levels were undetectable in all control animals in contrast to the uremic group (3.18 ± 0.62, 2.58 ± 0.54 and 1.86 ± 0.47 pg/ml, respectively, on days 7, 30 and 60; p < 0.05 at all time points). Similarly, uremic rats presented an increase in ET levels (0.038 ± 0.007 EU/ml) when compared to sham-operated animals (0.008 ± 0.006 EU/ml; p < 0.05). During the study, TNF-α levels in U + SC rats were significantly lower compared with U-control animals (p < 0.05). Similarly, ET levels in U + SC rats were lower when compared with U-control rats (p < 0.005). Conclusion: In conclusion, induction of renal failure triggered inflammation and induced endotoxemia in this experimental model of chronic kidney disease, which were reduced by sevelamer treatment. This data suggests that sevelamer carbonate induces an anti-inflammatory effect in parallel to a reduction in ET.

Association Between Body Mass Index and Body Fat in Chronic Kidney Disease Stages 3 to 5, Hemodialysis, and Peritoneal Dialysis Patients

OBJECTIVE Chronic kidney disease (CKD) patients may present with altered body composition. Body mass index (BMI) is a simple method for evaluating body fat mass (FM) in the general population. In CKD patients, there are few reports demonstrating the association between BMI and body composition. Our objective was to investigate the reliability of BMI as an indicator of FM in patients with CKD stages 3 to 5. METHODS Seventy-eight nondiabetic CKD patients (aged 48, SD +/- 12 years; 45% male) and 30 healthy control subjects (aged 46, SD +/- 12 years; 40% male), matched for age and sex, were evaluated. Chronic kidney disease patients were divided, according to K/DOQI guidelines, into 27 subjects at stages 3 to 4 (mean glomerular filtration rate of 43 +/- 12 mL/minute; age, 52 +/- 10 years), and 51 at stage 5: 25 in hemodialysis (HD) (aged 45, SD +/- 12 years; 44% male), and 26 in peritoneal dialysis (PD) (aged 49, SD +/- 13 years; 42% male). Body mass index was calculated as weight/height(2), and body composition was evaluated through dual-energy x-ray absorptiometry. RESULTS There was no difference in median BMI (kg/m(2)) among healthy control subjects (24.8; range, 19.2-34.1), CKD stages 3 to 4 (26.4; range, 20.4-37.6), HD patients (24.5; range, 19.4-35.7), and PD patients (24.5; range, 20.2-37.7; P > .05). Likewise, no significant difference was verified in median body FM (kg) among control subjects (18.8; range, 9.2-36.5), CKD stages 3 to 4 (21.2; range, 11.6-37.9), HD patients (17.1; range, 4.8-38.9), and PD patients (20.1; range, 6.5-41.5; P > .05). Moreover, a positive and significant correlation was found between BMI and FM (kg) in CKD stages 3 to 4 (Rho = 0.67, P = .0002), in HD patients (Rho = 0.67, P = .0002), in PD patients (Rho = 0.79, P < .0001), and in control subjects (Rho = 0.79, P < .0001). Although BMI and lean body mass (in kg) was significantly correlated in CKD stages 3 to 4 (Rho = 0.58, P = .001) and healthy control subjects (Rho = 0.30, P = .007), no significant correlation was found in HD patients (Rho = 0.19, P = .34) and in PD patients (Rho = 0.17, P = .38). CONCLUSIONS Body composition did not differ in patients with CKD stages 3 to 5, and between dialysis modalities. Although BMI was strongly and significantly correlated with body FM in CKD patients at stages 3 to 5, lean body mass was not. These findings suggest that BMI is a reliable indicator of body FM in this CKD population.

Evaluation of Salt Intake, Urinary Sodium Excretion and Their Relationship to Overhydration in Chronic Kidney Disease Patients

The purpose of this study was to estimate sodium intake in a group of patients with chronic kidney disease (CKD) and to correlate the results with the urinary excretion values of sodium and signs of fluid overload. We included patients with CKD in different stages. Urinary sodium was measured in 24 h urine samples. Body composition monitor (BCM) was used to estimate the hydration status. Sixty patients (38 ± 15 ml/min of GFR) presented 4.14 ± 1.71 g/24 h of urinary sodium excretion. Overhydration was detected in 50% of the patients by the BCM. There was a positive correlation between the measured sodium excretion values and BCM, ICW, ECW and TBW. In conclusion, markers of overhydration evaluated by BCM were positively correlated with urinary sodium excretion.

Lack of Adequate Predialyis Care and Previous Hemodialysis, but Not Hemoglobin Variability, Are Independent Predictors of Anemia-Associated Mortality in Incident Brazilian Peritoneal Dialysis Patients: Results from the BRAZPD Study

Background/Aims: The objective of this study was to analyze the prevalence of anemia and variability of hemoglobin (Hb) values in peritoneal dialysis (PD) patients, to establish its associated factors and their impact on clinical outcomes in a large cohort of patients starting PD treatment. Methods: Data were collected monthly in incident patients, who were followed until the primary endpoint (death from all causes) or until leaving the study. Results: 2,156 patients starting PD were included. The prevalence of Hb lower than 11 g/dl was 57% at baseline and decreased to 38% at the 4th month. Lack of adequate predialysis care and previous treatment with hemodialysis were the most important factors associated with anemia. Anemia was an independent predictor of mortality. There were no differences in patient survival throughout the different groups of Hb variability. Conclusion: Our data point to the need of identifying other risk factors for anemia and aggressively interfere with the modifiable ones in order to correct anemia and decrease mortality in this group of high-risk patients.

Soro urêmico inibe a expressão in vitro da quimiocina SDF-1: possível impacto da toxicidade urêmica na lesão endotelial

Introducao: A disfuncao endotelial e importante na patogenese da doenca cardiovascular (DCV) relacionada a doenca renal cronica (DRC). Stromal cell-derived factor-1 (SDF-1) e uma quimiocina que mobiliza celulas endoteliais progenitoras (EPC) e em conjunto com a interleucina-8 (IL-8) podem ser usadas como marcadores de reparo e lesao tecidual. Objetivo: Neste trabalho, foi investigado o efeito do meio uremico na expressao de SDF-1 e IL-8 in vivo e in vitro. Metodos: A inflamacao sistemica foi avaliada por meio da proteina C-reativa [...]INTRODUCTION Endothelial dysfunction is important in the pathogenesis of cardiovascular disease (CVD) related to chronic kidney disease (CKD). Stromal cell-derived factor-1 (SDF-1) is a chemokine which mobilizes endothelial progenitor cells (EPC) and together with interleukin-8 (IL-8) may be used as markers of tissue injury and repair. OBJECTIVE This study investigated in vivo and in vitro the effect of uremic media on SDF-1 and IL-8 expression. METHODS Systemic inflammation was assessed by C-reactive protein (CRP) and interleukin-6 (IL-6). IL-8 and SDF-1 were measured as markers of endothelial dysfunction and tissue repair, respectively, by ELISA. In vitro studies were performed on human umbilical vein endothelial cells (HUVEC) exposed to healthy or uremic media. RESULTS The study included 26 hemodialysis (HD) patients (17 ± 3 months on dialysis, 52 ± 2 years, 38% men and 11% diabetic). Serum concentrations of CRP, IL-6, SDF-1 and IL-8 were 4.9 ± 4.8 mg/ml, 6.7 ± 8.1 pg/ml, 2625.9 ± 1288.6 pg/ml and 128.2 ± 206.2 pg/ml, respectively. There was a positive correlation between CRP and IL-6 (ρ = 0.57, p < 0.005) and between SDF-1 and IL-8 (ρ = 0.45, p < 0.05). In vitro results showed that after 6 hours treatment, SDF-1 expression by HUVEC treated with uremic media is lower compared to cells treated with healthy media (p < 0.05). After 12 hours of treatment there was an increase in IL-8 when HUVECs were exposed to uremic media (p < 0.005). CONCLUSION We suggest that SDF-1 and IL-8 in HD patients can be used to measure the extent of damage and subsequent vascular activation in uremia.