Provision of Antioxidant Therapy in Hemodialysis (PATH)

Himmelfarb, Jonathan; İkizler, T. Alp; Ellis, Charles D.; Wu, Pingsheng; Shintani, Ayumi; Dalal, Sanjay; Kaplan, Mark; Chonchol, Michel; Hakim, Raymond M.

doi:10.1681/asn.2013050545

Cited by 62 publications

(54 citation statements)

References 57 publications

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“…101 Whether the oxidative stress of uremia is a primary driver of CVD or a secondary phenomenon is unclear. Small randomized trials in ESRD patients have not shown any significant benefit of antioxidant treatment, 102 suggesting that oxidative stress may not be a primary mediator of cardiovascular risk. Alternatively, targets and interventions that are more specific for uremia related oxidative stress should be studied.…”

Section: Oxidative Stressmentioning

confidence: 99%

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

2016

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Abstract-Patients with chronic kidney disease and end-stage renal disease are at 5-to 10-fold higher risk for developing cardiovascular disease (CVD) than age-matched controls. Clinically, CVD in this population manifests as coronary artery disease, arrhythmias, stroke, or congestive heart failure. Beyond the traditional risk factors (eg, diabetes mellitus and hypertension), uremia-specific factors that arise from accumulating toxins also contribute to the pathogenesis of CVD.In this review, we summarize the literature on the epidemiology of both traditional and uremia-related CVD and focus on postulated mechanisms of the latter. P. Jousset, MD, 1 describing common causes of death among patients with Bright disease C hronic kidney disease (CKD) is an increasingly urgent public health concern that is projected to grow worldwide at a rate of 8% annually, with the fastest growth expected in developing nations.2,3 It has long been known that patients with kidney failure are predisposed to cardiovascular disease (CVD) that manifests clinically in various forms, including coronary artery disease, atrial or ventricular arrhythmias, myocardial infarction, stroke, or congestive heart failure. Over the last 30 years, it has become clear that the risk of CVD increases early in the course of progressive kidney disease and that the epidemiology, pathophysiology, prevention, and treatment of CVD and CKD are closely related and interdependent. 4 In this review, we initially describe the epidemiology of CVD among people with CKD, noting the limitations of available research. We then discuss common risk factors for CVD (traditional and nontraditional) and key shared aspects of its pathophysiology with CKD. Next we describe emerging diagnostic tools and novel therapies that may help to delay or prevent end-stage renal disease (ESRD) and to curtail the escalating burden of cardiorenal disease. In the final section, we discuss the health services and health policy challenges that CKD and its inextricably linked CVD morbidities pose worldwide, particularly for low-and middle-income countries (LMICs). Phenotypes and Epidemiology of CVD in Patients With CKDPatients with CKD and some forms of CVD share a number of risk factors and underlying pathophysiological mechanisms that, by virtue of their similarities, offer opportunities to improve their management. The epidemiology of 4 of the commonest clinical phenotypes of CVD associated with CKD is discussed below. Coronary Artery DiseaseCoronary artery disease (CAD) is a leading cause of death among people with advanced CKD. Clinical syndromes compatible with CAD (including angina and myocardial infarction) are exceedingly common in patients with nondialysis-dependent CKD, and the incidence of myocardial

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Section: Oxidative Stressmentioning

confidence: 99%

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

2016

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“…When administered to CKD patients, LA improved some biomarkers, but not the oxidative stress biomarkers. [7][8][9]11,12 This lack of antioxidant effect of LA may be due to the fact that the tested groups were in the later stages of CKD, a condition where uremia is maximal. If uremic toxins have indeed a role in Nrf2 inactivation, LA supplementation should be started before the installation of uremia.…”

Section: Discussionmentioning

confidence: 99%

“…Although some studies showed that oral administration of LA, particularly to hemodialysis (HD) patients for several weeks, led to an improvement in asymmetric dimethylarginine (ADMA) 7 and C-reactive protein 8 levels, or erythropoietin resistance index, 9 oxidative stress biomarkers levels were not altered in the LA-treated groups of CKD 10 or HD patients. 8,9,11,12 In experimental CKD, intraperitoneally-injected LA for 8 weeks has been shown to improve blood pressure, renal function, and oxidative markers after 5/6 nephrectomy in rats, 13 while oral LA for 8 weeks decreased blood pressure, as well as vascular injury 14 when compared with the non-treated nephrectomized rats. In acetaminophen-induced uremia, orally-fed LA for 15 days prevented an increase in plasma urea, creatinine, and malondialdehyde levels in rats.…”

Section: Introductionmentioning

confidence: 99%

Lipoic acid does not improve renal function markers in 5/6 nephrectomy model: possible role of Nrf2 inactivation

Lin

Soares

et al. 2016

Renal Failure

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Chronic kidney disease (CKD) progression and complications are associated with increased oxidative stress, as well as with Nrf2 inactivation. Lipoic acid (LA) has been considered an inducer of Nrf2 antioxidant response. We tested whether oral administration of LA provides beneficial effects in experimental CKD in rats. Wistar rats underwent 5/6 nephrectomy (CKD group) or sham laparotomy. Seven days later, CKD group was divided into three subgroups that received: (i) LA continuously in the drinking water (100 mg/kg/day), (ii) LA by gavage every other day (100 mg/kg), or (iii) no LA treatment. LA treatment lasted until day 60. Plasma urea and creatinine, 24 hproteinuria, glomerulosclerosis, interstitial fibrosis/tubular atrophy, and Nrf2 activation were analyzed. All parameters measured were significantly altered in the untreated CKD group, compared with the sham group, as expected. Oral LA administration, either in the drinking water or by gavage, did not improve significantly any parameter, comparing the treated-groups with the untreated CKD group. These results indicate that oral LA administration for 53 days was ineffective to reactivate Nrf2 in the remnant kidney of uremic rats, likely preventing improvements in biochemical and histopathological markers of renal function. ARTICLE HISTORY

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“…Several lines of evidence have suggested that increased oxidative stress is highly prevalent in patients receiving dialysis, contributing to the increased incidence of the adverse outcomes [4]. Two previous randomized, placebo-controlled trials of patients undergoing hemodialysis have shown positive effects of antioxidant therapy on the development of ASCVDs [5,6], despite a number of unsuccessful clinical trials using a range of interventions aimed to improve the prognosis in this population [4,7].…”

Section: Introductionmentioning

confidence: 99%

Association of serum bilirubin levels with mortality in patients with diabetes initiating chronic hemodialysis: a competing risks analysis of a single-center cohort

et al. 2016

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Background: Evidence remains scarce regarding the property of serum bilirubin levels as a prognostic factor for the incidence of mortality in dialysis patients. Here, we aimed to examine the association between serum bilirubin levels and mortality in patients with diabetes initiating hemodialysis. Methods: This was a single-center, observational, historical cohort study of 395 Japanese patients with diabetes initiating chronic hemodialysis. There were 98 women and 297 men, and the mean (±SD) age was 61 ± 12 years. Patients were dichotomized at the baseline median level of serum bilirubin (0.3 mg/dL). The endpoints were the incidence of all-cause and cause-specific mortality. Hazard ratios for these endpoints were estimated using the Fine-Gray subdistribution hazard model and cause-specific hazard model because of the presence of competing risks. Results: During a median follow-up period of 3.9 years (range; 0.0-10.7 years), there were 83 cases of death, consisting of 39 and 44 cases from atherosclerotic cardiovascular diseases (ASCVDs) and non-ASCVDs, respectively. In the multivariate competing risks analysis, patients with lower bilirubin levels were associated with higher risk of ASCVD-related mortality (subdistribution hazard ratio 3.57, p = 0.015) but not with non-ASCVD-related mortality (0.83, p = 0.665) than those with higher bilirubin levels. Analysis treating bilirubin levels as a continuous variable, as well as cause-specific models yielded the similar results. Conclusions: Lower serum levels of bilirubin may be predictive of higher risk of ASCVD-related mortality in patients with diabetes initiating chronic hemodialysis. There was no relationship between levels of bilirubin and non-ASCVD-related mortality.

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Provision of Antioxidant Therapy in Hemodialysis (PATH)

Cited by 62 publications

References 57 publications

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

Lipoic acid does not improve renal function markers in 5/6 nephrectomy model: possible role of Nrf2 inactivation

Association of serum bilirubin levels with mortality in patients with diabetes initiating chronic hemodialysis: a competing risks analysis of a single-center cohort

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