Sérgio Gardano Elias Bucharles

Diastolic heart failure in dialysis patients: mechanisms, diagnostic approach, and treatment.

Heart failure (HF) is very common in the general population, and risk factors for HF, such as coronary artery disease, diabetes, obesity, and hypertension, are frequently present in patients with CKD. Therefore, HF is also an important cause of morbidity and mortality in this population. Diastolic heart failure (DHF), also called HF with preserved ejection fraction, refers to a clinical syndrome in which patients have symptoms and signs of HF, normal or near normal left ventricular (LV) systolic function, and evidence of diastolic dysfunction (e.g., abnormal LV filling and elevated filling pressure). Recent data suggest that HF with normal ejection fraction is even more common in patients than HF with low ejection fraction, including those on hemodialysis. Not surprisingly, DHF is a strong predictor of death in CKD patients. In this article, we review the information available on the mechanisms, clinical presentation, impact, and potential interventions in DHF based on evidence from CKD patients, as well as evidence from the general population potentially applicable to the CKD population.

Impact of Cholecalciferol Treatment on Biomarkers of Inflammation and Myocardial Structure in Hemodialysis Patients Without Hyperparathyroidism

INTRODUCTION Vitamin D (25-hydroxyvitamin D, 25(OH)D) deficiency, hypovitaminosis D, is highly prevalent in chronic kidney disease patients and is potentially involved with complications in the hemodialysis (HD) population. The aim of this study was to evaluate the impact of cholecalciferol supplementation on biomarkers of mineral metabolism, inflammation, and cardiac function in a group of HD patients presenting with hypovitaminosis D and low intact parathyroid hormone (iPTH) levels. MATERIAL AND METHODS HD patients with iPTH levels of <300 pg/mL, not receiving vitamin D therapy, and presenting with 25(OH)D levels of <30 ng/mL were enrolled in this prospective study. Oral cholecalciferol was prescribed once a week in the first 12 weeks (50,000 IU) and in the last 12 weeks (20,000 IU) of the study. High-sensitivity C-reactive protein, interleukin-6, and serum albumin were used as inflammatory markers. Echocardiograms were performed on a midweek interdialytic day at baseline and after 6 months of cholecalciferol supplementation. RESULTS In all, 30 patients were included in the final analysis. We observed a significant increase in serum 25(OH)D levels after 3 months (46.2 ± 14.4 ng/mL vs. 18.1 ± 6.6 ng/mL; P < .001) and after 6 months (40.4 ± 10.4 ng/mL vs. 18.1 ± 6.6 ng/mL; P < .001) of cholecalciferol supplementation. There were no significant changes in alkaline phosphatase, iPTH, phosphorus, and serum albumin levels, but there was a slight but significant increase in calcium levels after 6 months of cholecalciferol supplementation (9.4 ± 0.6 mg/dL vs. 9.0 ± 0.6 mg/dL; P = .02). Additionally, we observed a significant reduction in high-sensitivity C-reactive protein levels after 3 months (median: 0.62 [0.05 to 29.6] mg/L vs. 0.32 [0.02 to 3.13] mg/L; P = .02) and after 6 months (median: 0.62 [0.05 to 29.6] mg/L vs. 0.50 [0.02 to 5.66] mg/L; P = .04) of cholecalciferol supplementation, as well as a significant reduction in interleukin-6 levels (median: 6.44 pg/mL vs. 3.83 pg/mL; P = .018) after 6 months of supplementation. Left ventricular mass index was significantly reduced at the end of supplementation (159 ± 55 g/m(2) vs. 175 ± 63 g/m(2); P = .03). CONCLUSIONS Cholecalciferol supplementation in HD patients was found to be safe and efficient to correct hypovitaminosis D and established little impact on mineral metabolism markers. Additionally, we observed a reduction in important surrogate markers of cardiovascular risk, namely systemic inflammation and left ventricular hypertrophy, suggesting an anti-inflammatory action and possibly an improvement of cardiac dysfunction.

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.

Immune Mechanisms Involved in Cardiovascular Complications of Chronic Kidney Disease

A sustained status of chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular degeneration, myocardial fibrosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. These consequences of a chronically activated immune system impact on the acceleration of atherosclerosis, vascular calcification and development of heart dysfunction. Recent evidence suggests that these immune-mediated consequences of uremic toxicity are not only important to stratify the risk and understand the mechanisms of disease, but also represent an important area for intervention. Thus, the aim of this brief review is to discuss the immune mechanisms behind atherosclerosis and myocardiopathy in CKD. We also display the emerging evidence that strategies focusing on modulating the immune response or reducing the generation of triggers of inflammation may represent an important tool to reduce mortality in this group of patients. Ongoing studies may generate the evidence that will translate these strategies to definitive changes in clinical practice.

Hypovitaminosis D Is Associated with Systemic Inflammation and Concentric Myocardial Geometric Pattern in Hemodialysis Patients with Low iPTH Levels

Background: Vitamin D [25(OH)D] deficiency is a cardiovascular risk factor in the hemodialysis (HD) population. The aim of this study was to identify hypovitaminosis D in HD patients without signs of hyperparathyroidism and to analyze its association to inflammation and echocardiographic alterations. Methods: Patients on HD with iPTH <300 pg/ml not receiving vitamin D therapy were recruited. Hypovitaminosis D was defined as 25(OH)D <30 ng/ml. High-sensitivity C-reactive protein, interleukin-6 and serum albumin were used as inflammation markers. Echocardiograms were performed in an interdialytic mid-week day. Results: Sixty-one patients (mean age of 56 ± 15 years, 52% males, 93% Caucasians, 31% diabetic) were included, and 75% presented hypovitaminosis D. Inflammation was more prevalent among those with hypovitaminosis D, and these patients presented higher relative wall thickness (0.48 ± 0.11 vs. 0.42 ± 0.10 mm; p = 0.05) and lower left ventricular diastolic (49.8 ± 6.2 vs. 54.7 ± 5.8 mm; p = 0.013) and systolic (31.9 ± 5.7 vs. 36.8 ± 7.2 mm; p = 0.012) diameters. Conclusions: Hypovitaminosis D is associated with inflammation and concentric geometric pattern of the left ventricle, even in the absence of high iPTH levels. Vitamin D repletion (aiming to reduce cardiovascular complications) should also be considered in HD patients with normal or low iPTH levels.

Prevalence and prognostic impact of diastolic dysfunction in patients with chronic kidney disease on hemodialysis

FUNDAMENTO: Disfuncao diastolica e frequente em pacientes de hemodialise, mas seu impacto na evolucao clinica e incerto. OBJETIVO: Avaliar a prevalencia e o impacto prognostico da disfuncao diastolica (DD) avancada (DDA) do ventriculo esquerdo (VE) em pacientes de hemodialise. METODOS: Ecocardiogramas foram realizados em pacientes no primeiro ano de hemodialise, em ritmo sinusal, sem doenca cardiovascular manifestada, excluindo-se aqueles com valvopatia significativa ou derrame pericardico. Pela avaliacao integrada dos dados ecodopplercardiograficos, a funcao diastolica foi classificada como: 1) normal, 2) DD discreta (alteracao do relaxamento) e 3) DDA (pseudonormalizacao e fluxo restritivo). Os desfechos pesquisados foram mortalidade geral e eventos cardiovasculares. RESULTADOS: Foram incluidos 129 pacientes (78 homens), com idade 52 ± 16 anos e prevalencia de DD de 73% (50% com DD discreta e 23% com DDA). No grupo com DDA, demonstrou-se maior idade (p < 0,01), pressao arterial sistolica (p < 0,01) e diastolica (p = 0,043), massa do VE (p < 0,01), indice do volume do atrio esquerdo (p < 0,01) e proporcao de diabeticos (p = 0,019), alem de menor fracao de ejecao (p < 0,01). Apos 17 ± 7 meses, a mortalidade geral foi significativamente maior naqueles com DDA, em comparacao aos normais e com DD discreta (p = 0,012, log rank test). Na analise multivariada de Cox, a DDA foi preditiva de eventos cardiovasculares (hazard ratio 2,2, intervalo de confianca 1,1-4,3, p = 0,021) apos ajuste para idade, genero, diabete, massa do VE e fracao de ejecao. CONCLUSAO: A DDA subclinica foi encontrada em aproximadamente um quarto dos pacientes de hemodialise e acarretou impacto prognostico, independente de outros dados clinicos e ecocardiograficos.BACKGROUND Diastolic dysfunction (DD) is frequent in patients on hemodialysis (HD), but its impact on the clinical evolution is yet to be established. OBJECTIVE To evaluate the prevalence and prognostic impact of left ventricular (LV) advanced diastolic dysfunction (ADD) in patients on hemodialysis. METHODS The echocardiograms were performed during the first year of HD therapy, in patients with sinus rhythm, with no evidence of cardiovascular disease, excluding those with significant valvopathy or pericardial effusion. The combined assessment of the Doppler echocardiographic data classified the diastolic dysfunction as: 1) normal diastolic function; 2) mild DD (relaxation alteration) and 3) ADD (pseudonormalization and restrictive flow pattern). The assessed outcomes were general mortality and cardiovascular events. RESULTS A total of 129 patients (78 males), aged 52 +/- 16 years, with a DD prevalence of 73% (50% with mild DD and 23% with ADD) were included in the study. The group with ADD was older (p < 0.01) and presented higher systolic (p < 0.01) and diastolic BP (p = 0.043), LV mass (p < 0.01), left atrial volume index (p < 0.01) and number of diabetic patients (p = 0.019), as well as lower ejection fraction (EF) (p < 0.01). After 17 +/- 7 months, the general mortality was significantly higher in individuals with ADD, when compared to those with normal function and mild DD (p = 0.012, log rank test). At Cox multivariate analysis, ADD was predictive of cardiovascular events (hazard ratio 2.2; confidence interval: 1.1-4.3; p = 0.021) after adjusted for age, gender, diabetes, LV mass and EF. CONCLUSION The subclinical ADD was identified in approximately 25% of the patients undergoing hemodialysis and had a prognostic impact, regardless of other clinical and echocardiographic data.

Prevalência e impacto prognóstico da disfunção diastólica na doença renal crônica em hemodiálise

FUNDAMENTO: Disfuncao diastolica e frequente em pacientes de hemodialise, mas seu impacto na evolucao clinica e incerto. OBJETIVO: Avaliar a prevalencia e o impacto prognostico da disfuncao diastolica (DD) avancada (DDA) do ventriculo esquerdo (VE) em pacientes de hemodialise. METODOS: Ecocardiogramas foram realizados em pacientes no primeiro ano de hemodialise, em ritmo sinusal, sem doenca cardiovascular manifestada, excluindo-se aqueles com valvopatia significativa ou derrame pericardico. Pela avaliacao integrada dos dados ecodopplercardiograficos, a funcao diastolica foi classificada como: 1) normal, 2) DD discreta (alteracao do relaxamento) e 3) DDA (pseudonormalizacao e fluxo restritivo). Os desfechos pesquisados foram mortalidade geral e eventos cardiovasculares. RESULTADOS: Foram incluidos 129 pacientes (78 homens), com idade 52 ± 16 anos e prevalencia de DD de 73% (50% com DD discreta e 23% com DDA). No grupo com DDA, demonstrou-se maior idade (p < 0,01), pressao arterial sistolica (p < 0,01) e diastolica (p = 0,043), massa do VE (p < 0,01), indice do volume do atrio esquerdo (p < 0,01) e proporcao de diabeticos (p = 0,019), alem de menor fracao de ejecao (p < 0,01). Apos 17 ± 7 meses, a mortalidade geral foi significativamente maior naqueles com DDA, em comparacao aos normais e com DD discreta (p = 0,012, log rank test). Na analise multivariada de Cox, a DDA foi preditiva de eventos cardiovasculares (hazard ratio 2,2, intervalo de confianca 1,1-4,3, p = 0,021) apos ajuste para idade, genero, diabete, massa do VE e fracao de ejecao. CONCLUSAO: A DDA subclinica foi encontrada em aproximadamente um quarto dos pacientes de hemodialise e acarretou impacto prognostico, independente de outros dados clinicos e ecocardiograficos.BACKGROUND Diastolic dysfunction (DD) is frequent in patients on hemodialysis (HD), but its impact on the clinical evolution is yet to be established. OBJECTIVE To evaluate the prevalence and prognostic impact of left ventricular (LV) advanced diastolic dysfunction (ADD) in patients on hemodialysis. METHODS The echocardiograms were performed during the first year of HD therapy, in patients with sinus rhythm, with no evidence of cardiovascular disease, excluding those with significant valvopathy or pericardial effusion. The combined assessment of the Doppler echocardiographic data classified the diastolic dysfunction as: 1) normal diastolic function; 2) mild DD (relaxation alteration) and 3) ADD (pseudonormalization and restrictive flow pattern). The assessed outcomes were general mortality and cardiovascular events. RESULTS A total of 129 patients (78 males), aged 52 +/- 16 years, with a DD prevalence of 73% (50% with mild DD and 23% with ADD) were included in the study. The group with ADD was older (p < 0.01) and presented higher systolic (p < 0.01) and diastolic BP (p = 0.043), LV mass (p < 0.01), left atrial volume index (p < 0.01) and number of diabetic patients (p = 0.019), as well as lower ejection fraction (EF) (p < 0.01). After 17 +/- 7 months, the general mortality was significantly higher in individuals with ADD, when compared to those with normal function and mild DD (p = 0.012, log rank test). At Cox multivariate analysis, ADD was predictive of cardiovascular events (hazard ratio 2.2; confidence interval: 1.1-4.3; p = 0.021) after adjusted for age, gender, diabetes, LV mass and EF. CONCLUSION The subclinical ADD was identified in approximately 25% of the patients undergoing hemodialysis and had a prognostic impact, regardless of other clinical and echocardiographic data.

Avaliação e manejo da doença cardiovascular em pacientes com doença renal crônica

Cardiovascular disease is the leading cause of death in the set of chronic kidney disease (CKD) patients, whether on renal replacement therapy or conservative treatment. A better understanding of cardiovascular risk factors, diagnostic approach and management are central keys to develop strategies to reduce cardiovascular mortality among those patients. This review article discusses some aspects of pathophysiology, investigation methods and current treatment of cardiovascular disease in CKD patients.

Associação entre marcadores de inflamação e aumento do átrio esquerdo em pacientes de hemodiálise

BACKGROUND In individuals with concurrent chronic kidney disease (CKD) and cardiovascular disease (CVD), the association between left atrial volume (LAV) and serum levels of C-reactive protein (CRP) is shown. OBJECTIVE Verify the presence of associations between systemic inflammation and LA dilation in patients on hemodialysis (HD) without clinically evident CVD. METHODS This was an observational cross-sectional study of a population on HD (> 3 months), which excluded patients with acute or chronic inflammatory diseases (infections, malignancies, autoimmune diseases) hemodynamic instability, use of anti-inflammatory drugs, hyperparathyroidism, arrhythmias, mitral valve disease and prior cardiovascular (CV) events. CRP and interleukin-6 (IL-6) measurements as well as Doppler echocardiography were obtained. Correlation coefficients were determined to evaluate the associations between variables. RESULTS A total of 58 patients were included (28 men, aged 55 ± 15 years), on HD for 24 ± 16 months, 45% were hypertensive, 26% diabetic, with median CRP of 5.1 mg/dL and IL-6 of 6.1 pg/dL. CRP significantly correlated with LAV (p = 0.040), LAV index (LAVi, p = 0.02) and mitral inflow E wave (p = 0.014). IL-6, despite the strong association with CRP levels (r = 0.75, p < 0.001), did not correlate with echocardiographic indices. Individuals in the top quartile of CRP had significantly higher LAVi than the others (42 ± 17 versus 32 ± 11 mL/m², p = 0.015). CONCLUSIONS In subjects on HD with no prior CV event, there was an association between elevated CRP levels and LA enlargement. The findings suggest an association between physiopathological processes related to left atrial dilation and systemic inflammatory state of patients on HD.