Renato Watanabe

Impact of Cardiovascular Calcification in Nondialyzed Patients after 24 Months of Follow-up

BACKGROUND AND OBJECTIVES Coronary artery calcification (CAC) is highly prevalent among patients with chronic kidney disease (CKD), and it has been described as a strong predictor of mortality in the dialysis population. Because there is a lack of information regarding cardiovascular calcification and clinical outcomes in the earlier stages of the disease, we aimed to evaluate the impact of CAC on cardiovascular events, hospitalization, and mortality in nondialyzed patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This is a prospective study including 117 nondialyzed patients with CKD (age, 57 +/- 11.2 years; 61% male; 23% diabetics; creatinine clearance, 36.6 +/- 17.8 ml/min per 1.73 m(2)). CAC was quantified by multislice computed tomography. The occurrence of cardiovascular events, hospitalization, and death was recorded over 24 months. RESULTS CAC >10 Agatston units (AU) was observed in 48% of the patients [334 (108 to 858.5) AU; median (interquartiles)], and calcification score >or=400 AU was found in 21% [873 (436-2500) AU]. During the follow-up, the occurrence of 15 cardiovascular events, 19 hospitalizations, and 4 deaths was registered. The presence of CAC >10 AU was associated with shorter hospitalization event-free time and lower survival. CAC >or=400 AU was additionally associated with shorter cardiovascular event-free time. Adjusting for age and diabetes, CAC >or=400 AU was independently associated with the occurrence of hospitalization and cardiovascular events. CONCLUSIONS Cardiovascular events, hospitalization, and mortality were associated with the presence of CAC in nondialyzed patients with CKD. Severe CAC was a predictor of cardiovascular events and hospitalization in these patients.

Effect of rosuvastatin and sevelamer on the progression of coronary artery calcification in chronic kidney disease: a pilot study.

INTRODUCTION Coronary artery calcification (CAC) is highly prevalent among chronic kidney disease (CKD) patients and its strong association with mortality has been recognized early in the course of CKD. The aim of the present study was to test the effect of rosuvastatin and sevelamer hydrochloride on the progression of CAC in nondialyzed CKD patients. METHODS An open-label, randomized and controlled pilot study was conducted including 117 CKD patients (62% men, 56.9 ± 11.2 years, eGFR 36 ± 16.5 ml/min). Patients were randomly assigned to rosuvastatin (n = 38; 10 mg/day), to sevelamer hydrochloride (n = 38; 2,400 mg/day) and to control (n = 41) groups. CAC (by multislice computed tomography) and biochemical analyses were performed at baseline and after 24 months. RESULTS At baseline, CAC was observed in 55%, 58% and 61% of patients in the rosuvastatin, sevelamer hydrochloride and control groups, respectively (p = 0.87). Calcium score at baseline as well as its absolute and relative changes during 24 months were similar among the groups. Low density lipoprotein cholesterol (LDL-c) was higher and decreased significantly in the rosuvastatin group (p < 0.01). The analysis adjusting for LDL-c showed that the drug regimens were not associated with the progression of CAC (drug effect p = 0.85; time-effect p < 0.001; interaction p = 0.76). CONCLUSIONS Treatment with rosuvastatin and sevelamer hydrochloride may not delay the progression of CAC in non-dialysis dependent CKD patients.

Balance between cytokine production by peripheral blood mononuclear cells and reactive oxygen species production by monocytes in patients with chronic kidney disease.

Hemodialysis (HD) and peritoneal dialysis are associated with inflammatory events and immunological incompetence. The purpose of this study was to evaluate the effect of both uremia and dialysis modality on the production of cytokines and reactive oxygen species (ROS) by monocytes. four groups of subjects were studied: 28 chronic kidney disease (CKD) patients, 14 chronic HD patients, 14 patients on continuous ambulatory peritoneal dialysis (CAPD) patients, and 14 healthy volunteers. peripheral blood mononuclear cells (PBMC) were isolated from blood samples and incubated for 24 hr with or without lipopolysaccharide (LPS). TNF‐α and IL‐10 production by PBMC and serum levels of these cytokines were quantified by ELISA. Aliquots of whole blood were incubated in vitro and ROS production and phagocytosis were quantified by flow cytometry. Compared to the control group, Staphylococcus aureus–stimulated ROS production by monocytes was significantly lower in the HD group. The highest levels of unstimulated TNF‐α production in vitro were observed in the HD group. In the CKD group, as well as in the whole population, there were a negative correlation between TNF‐α production by unstimulated PBMC and ROS production by S. aureus–stimulated monocytes and a positive correlation between PMA‐stimulated ROS production by monocytes and unstimulated and LPS‐stimulated IL‐10 production by PBMC suggesting that the pro‐inflammatory state in CKD patients is associated with decreased response to infectious challenges.

Effects of Spermidine and p-Cresol on Polymorphonuclear Cell Apoptosis and Function

Polymorphonuclear leukocytes (PMNs) from chronic kidney disease (CKD) patients display accelerated apoptosis and dysfunction, which may predispose CKD patients to infections. In this study, we investigated the effect of spermidine and p-cresol on apoptosis and function on PMN from healthy subjects. We measured the effect of spermidine and p-cresol on apoptosis, ROS production unstimulated and stimulated (S. aureus and PMA) and expression of CD95, caspase 3, and CD11b on PMN. After incubation with p-cresol and spermidine, we did not observe any changes in apoptosis, viability or expression of caspase 3 and CD95 in PMN from healthy subjects. PMN incubated for 10 minutes with spermidine demonstrated a significant reduction in spontaneous, S. aureus and PMA-stimulated ROS production. p-cresol induced a decrease in PMA-stimulated ROS production. Spermidine and p-cresol also induced a decrease in the expression of CD11b on PMN. Spermidine and p-cresol decreased the expression of CD11b and oxidative burst of PMN from healthy subjects and had no effect on PMN apoptosis and viability.

Variação dos níveis de hemoglobina de pacientes em hemodiálise tratados com eritropoetina: uma experiência brasileira

OBJECTIVE: Correction of anemia using epoetin decreases morbidity and increases survival and quality of life in end-stage renal disease. Maintaining hemoglobin levels within the range proposed by guidelines has become a major challenge, with hemoglobin cycling affecting more than 90% of patients undergoing hemodialysis. The variability of hemoglobin levels over time was assessed in our patients. METHODS: Data were retrospectively collected on 249 patients undergoing hemodialysis over a 3-year period at seven centers in Brazil. Hemoglobin was measured at least monthly, and target levels were those between 10.5 g/dL and 12.5 g/dL. Patients were grouped into six categories of variability consistently low ( 12.5g/dL), low amplitude fluctuation with low hemoglobin levels, low amplitude fluctuation with high hemoglobin levels and high amplitude fluctuation. None of the patients maintained stable hemoglobin levels for the entire 36-month period. RESULTS: The mean monthly proportion of patients that had hemoglobin levels within the target range was 50% (range, 42% to 61%). Mean levels above the target (30%) were more frequent than those below it (20%). During 6, 12, and 36 months, proportions of patients with consistently low levels of hemoglobin decreased from 3.6% to 0%, from 31.7% to 2.8% for those with consistently high, from 7.6% to 0% for those with low amplitude fluctuation with low hemoglobin levels and from 41.3% to 8.3% for those with low amplitude fluctuation with high hemoglobin levels. However, the proportions of patients with high amplitude fluctuation increased from 21.5% to 88.9%. CONCLUSION: Maintaining hemoglobin levels within the target range is difficult, especially for longer periods of time. Missing the target seems more often due to levels above it, but high-amplitude fluctuations eventually occur in the majority of patients.

Avaliação da espessura médio-intimal em pacientes com doença renal crônica não dialítica: estudo prospectivo de 24 meses

INTRODUCTION Increased carotid intima-media thickness (IMT) is considered a marker of early-onset atherosclerosis and it seems to predict cardiovascular events in general population. The prognostic value of IMT in patients with early-stage chronic kidney disease (CKD) has not been clearly established. OBJECTIVE We aimed to evaluate the association between IMT and cardiovascular (CV) events and mortality in CKD patients. METHODS A cohort of CKD patients in stage 2-4 was evaluated the occurrence of CV events and death in a 24 months follow-up. Laboratory data, carotid ultrasound and coronary computed tomography were performed at baseline. RESULTS A total of 117 patients (57 ± 11 years-old, 61% male) were evaluated. Mean glomerular filtration rate (eGFR) was 36 ± 17 mL/min, 96% of patients had hypertension, 23% diabetes and 27% were obese. Coronary calcification was found in 48% of the patients, with higher prevalence among CKD stage 4 (p = 0.02). The median value of IMT was 0.6 mm (0.4-0.7 mm). When compared to patients with IMT ≤ 0.6 mm, those with IMT > 0.6 mm were older (p = 0.001), had higher prevalence of male (p = 0.001) and had lower eGFR (p = 0.01). These patients also had higher prevalence of coronary calcification (p = 0.001). During the follow-up, there were no differences in the occurrence of cardiovascular events and deaths between the two groups. CONCLUSION IMT in early-stage CKD patients was related to coronary calcification, but not with the occurrence of cardiovascular events or death.Introduction: Increased carotid intima-media thickness (IMT) is considered a marker of early-onset atherosclerosis and it seems to predict cardiovascular events in general population. The prognostic value of IMT in patients with early-stage chronic kidney disease (CKD) has not been clearly established. Objective: We aimed to evaluate the association between IMT and cardiovascular (CV) events and mortality in CKD patients. Methods: A cohort of CKD patients in stage 2-4 was evaluated the occurrence of CV events and death in a 24 months follow-up. Laboratory data, carotid ultrasound and coronary computed tomography were performed at baseline. Results: A total of 117 patients (57 ± 11 years-old, 61% male) were evaluated. Mean glomerular filtration rate (eGFR) was 36 ± 17 mL/min, 96% of patients had hypertension, 23% diabetes and 27% were obese. Coronary calcification was found in 48% of the patients, with higher prevalence among CKD stage 4 (p = 0.02). The median value of IMT was 0.6 mm (0.4-0.7 mm). When compared to patients with IMT ≤ 0.6 mm, those with IMT > 0.6 mm were older (p = 0.001), had higher prevalence of male (p = 0.001) and had lower eGFR (p = 0.01). These patients also had higher prevalence of coronary calcification (p = 0.001). During the follow-up, there were no differences in the occurrence of cardiovascular events and deaths between the two groups. Conclusion: IMT in early-stage CKD patients was related to coronary calcification, but not with the occurrence of cardiovascular events or death.

The association between coronary artery calcification progression and loss of bone density in non-dialyzed CKD patients.

BACKGROUND Coronary artery calcification (CAC) and low bone density are coexisting deleterious conditions commonly shared by chronic kidney disease (CKD) patients. In the present study, we aimed to investigate whether the progression of CAC was associated with overtime reduction in bone density in non-dialyzed CKD patients. METHODS This is a prospective study of 24 months including 72 non-dialyzed CKD patients Stages 2 - 4 (age 57.6 ± 10.3 years, 62% male, 22% diabetics). CAC and vertebral bone density (VBD) were measured by computed tomography. RESULTS At baseline, 46% of the patients had CAC (calcified group) and calcification was not identified in 54% of the patients (non-calcified group). The calcified group was older, predominantly male, and had lower VBD in comparison to non-calcified group. CAC progression was observed only in the calcified group (91% of the patients increased calcium score). The multiple regression analysis revealed loss of VBD as the independent determinant of CAC progression in these patients. CONCLUSIONS CAC progression was associated with loss of VBD in non-dialyzed CKD patients.

Asymptomatic Ventricular Arrhythmia and Clinical Outcomes in Chronic Kidney Disease: A Pilot Study

Background/Aims: Ventricular arrhythmia is associated with increased risk of cardiovascular events and death in the general population. Sudden death is a leading cause of death in end-stage renal disease. We aimed at evaluating the effects of ventricular arrhythmia on clinical outcomes in patients with earlier stages of chronic kidney disease (CKD). Methods: In a prospective study of 109 nondialyzed CKD patients (estimated glomerular filtration rate 34.8 ± 16.1 ml/min/1.73 m2, 57 ± 11.4 years, 61% male, 24% diabetics), we tested the hypothesis that the presence of subclinical complex ventricular arrhythmia, assessed by 24-hour electrocardiogram, is associated with increased risks of cardiovascular events, hospitalization, and death and with their composite outcome during 24 months of follow-up. Complex ventricular arrhythmia was defined as the presence of multifocal ventricular extrasystoles, paired ventricular extrasystoles, nonsustained ventricular tachycardia, or R wave over T wave. Results: We identified complex ventricular arrhythmia in 14% of participants at baseline. During follow-up, 11 cardiovascular events, 15 hospitalizations, and 4 deaths occurred. The presence of complex ventricular arrhythmia was associated with cardiovascular events (p < 0.001), hospitalization (p = 0.018), mortality (p < 0.001), and the composite outcome (p < 0.001). In multivariate Cox regression analysis, adjusting for demographic characteristics, complex ventricular arrhythmia was associated with increased risk of the composite outcome (HR 4.40; 95% CI 1.60-12.12; p = 0.004). Conclusion: In this pilot study, the presence of asymptomatic complex ventricular arrhythmia was associated with poor clinical outcomes in nondialyzed CKD patients.

Impact of treatment modality, biochemical parameters and apoptosis on polymorphonuclear cell (PMN) function in patients with renal failure

It has been suggested that PMN apoptosis is increased in dialysis patients and may contribute to cellular dysfunction. We investigated the effect of treatment modality and biochemical parameters on PMN apoptosis and function. Blood was drawn from 17 controls, 17 patients with chronic renal failure (CRF; creatinine clearance 28 ± 14 ml/min/1.73 m2), 10 hemodialysis (HD) and 11 CAPD patients. Upon collection, whole blood aliquots were incubated in RPMI-1640 with propidium iodide (PI)-labeled Saureus (SA), PMA, fMLP or LPS for 30 min. Cells were then stained with DCFH-DA and analyzed by flow cytometry, in order to quantify phagocytosis and H2O2 release by PMN. After separation by gradient centrifugation, PMN were stained with Annexin-V and PI in order to quantify apoptosis by flow cytometry. The results were correlated with blood levels of urea, creatinine, bicarbonate, albumin and PTH. Results are presented as means ± SD. Among CRF and HD patients, there was an inverse correlation between apoptosis and SA- (r = 0.62, P = 0.01 and r = 0.89, P = 0.02, respectively) and LPS-stimulated H2O2 release (r = 0.68, P = 0.005 and r = 0.61, P = 0.058, respectively). No biochemical parameters correlated with apoptosis or cellular functions. In summary, PMN apoptosis contributes to cellular malfunction in uremia, but does not account for all the dysfunction. Hence, it is possible that other uremic toxins affect cell performance independently of apoptosis. Table