Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators

Shafi, Tariq; Meyer, Timothy W.; Hostetter, Thomas H.; Melamed, Michal L.; Parekh, Rulan S.; Hwang, Seungyoung; Banerjee, Tanushree; Coresh, Josef; Powe, Neil R.

doi:10.1371/journal.pone.0126048

Cited by 76 publications

(70 citation statements)

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“…Phenylacetylglutamine is also generated exclusively and hippurate partially through the action of colon microbes. Prior studies, including our work, also suggest that phenylacetylglutamine retention may also contribute to cardiovascular events in patients on hemodialysis 5 and also in patients with earlier stages of chronic kidney disease. 6 All these solutes share the property that they are cleared largely by secretion in the normal kidney.…”

Section: Introductionsupporting

confidence: 69%

“…Our findings of the overall lack of association between these solutes and outcomes despite adequate statistical power (Table 3) contradict some prior epidemiological studies of chronic kidney disease and dialysis patients, 13, 16 including some of our own prior work. 5 We previously reported that among incident hemodialysis participants of the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study, free (but not total) p-cresol sulfate and free phenylacetylglutamine were associated with cardiovascular mortality, whereas there was no association with outcomes noted with total or free indoxyl sulfate. 5, 17 Although in our HEMO analyses, the overall associations of p-cresol sulfate and indoxyl sulfate with mortality were negative, we noticed statistically significant interactions in our sub-group analyses.…”

Section: Discussionmentioning

confidence: 97%

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Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Shafi

Sirich

Meyer

et al. 2017

Kidney International

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Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dL), a two-fold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98–1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06–1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

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Section: Introductionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 97%

Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Shafi

Sirich

Meyer

et al. 2017

Kidney International

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“…107 Some have speculated that the asymmetrical dimethylarginine pathway contributes to endothelial dysfunction and progression of atherosclerosis; however, treatment with sildenafil or l-arginine to restore impaired nitric oxide signaling has failed to reverse CVD. 108,109 Finally, increased circulating levels of uremic solutes such as p-cresol sulfate and phenylacetylglutamine have been associated with higher cardiovascular morbidity and mortality in patient with ESRD, 110 but it is not known whether removal or blocking these uremic toxins will lead to improved cardiovascular outcomes.…”

Section: February 2 2016mentioning

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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“…We observed substantial interindividual variability of intestinal uptake of PAG, albeit without a clear influence of renal function, thus also contributing to the wide dispersion of individual serum levels of PAG as already shown for p-cresyl sulfate and indoxyl sulfate. 23 In patients with mild to moderate CKD, serum PAG was strongly related to overall mortality and cardiovascular disease, even when adjusted for age, sex, presence of diabetes mellitus, 24 In addition, the association between serum solute levels and adverse outcomes was as least as strong for PAG as for free p-cresyl sulfate, highlighting the relevance of solutes with a microbial origin and highly efficient tubular secretion, irrespective of protein binding. Whether PAG itself is a true uremic toxin remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD

Poesen

Claes

Evenepoel

et al. 2016

JASN

151

125

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Colonic microbial metabolism substantially contributes to uremic solute production. p-Cresyl sulfate and indoxyl sulfate are the main representatives of solutes of microbial origin and also, protein-bound solutes, exhibiting high protein-binding affinity and dependence on tubular secretion. Phenylacetylglutamine is another microbial metabolite with high dependence on tubular secretion but low protein-binding affinity. The relevance of such solutes is unknown. Therefore, we prospectively followed 488 patients with CKD stages 1-5 and a measurement of serum phenylacetylglutamine by liquid chromatography-mass spectrometry. In a subgroup, we determined 24-hour urinary excretion as a surrogate of intestinal uptake as well as renal clearance of phenylacetylglutamine. We performed outcome analysis for mortality (51 events) and cardiovascular disease (75 events). Serum phenylacetylglutamine level correlated with 24-hour urinary excretion (rho=0.55; P,0.001) and clearance of phenylacetylglutamine (rho=20.76; P,0.001). Phenylacetylglutamine clearance also correlated with eGFR (rho=0.84; P,0.001). Furthermore, serum phenylacetylglutamine level associated with mortality (hazard ratio per 1-SD increase, 1.77; 95% confidence interval, 1.22 to 2.57; P=0.003) and cardiovascular disease (hazard ratio, 1.79; 95% confidence interval, 1.32 to 2.41; P,0.001) after adjustment for age, sex, presence of diabetes mellitus, prior cardiovascular disease, and eGFR. Thus, serum phenylacetylglutamine level is elevated in patients with more advanced CKD and determined by intestinal uptake and renal clearance, and it is not fully accounted for by differences in eGFR. High serum phenylacetylglutamine level is a strong and independent risk factor for mortality and cardiovascular disease, suggesting the relevance of microbial metabolism and/or tubular dysfunction in CKD, irrespective of protein binding.

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Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators

Cited by 76 publications

References 48 publications

Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD

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