Cardiovascular disease causes over 50% of the deaths in dialysis patients, and the risk of death is higher in white than in black patients. The underlying mechanisms for these findings are unknown. We determined the association of the proatherogenic metabolite trimethylamine N-oxide (TMAO) with cardiovascular outcomes in hemodialysis patients and assessed whether this association differs by race. We measured TMAO in stored serum samples obtained 3-6 months after randomization from a total of 1232 white and black patients of the Hemodialysis Study, and analyzed the association of TMAO with cardiovascular outcomes using Cox models adjusted for potential confounders (demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Mean age of the patients was 58 years; 35% of patients were white. TMAO concentration did not differ between whites and blacks. In whites, 2-fold higher TMAO associated with higher risk (hazard ratio [95% confidence interval]) of cardiac death (1.45 [1.24 to 1.69]), sudden cardiac death [1.70 (1.34 to 2.15)], first cardiovascular event (1.15 [1.01 to 1.32]), and any-cause death (1.22 [1.09 to 1.36]). In blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentrations below the median (1.58 [1.03 to 2.44]). Compared with blacks in the same quintile, whites in the highest quintile for TMAO (≥135 μM) had a 4-fold higher risk of cardiac or sudden cardiac death and a 2-fold higher risk of any-cause death. We conclude that TMAO concentration associates with cardiovascular events in hemodialysis patients but the effects differ by race.

Background and ObjectivesNumerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney — p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine — with outcomes in hemodialysis patients.Design, Setting, Participants and MeasurementsWe measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/VUREA.ResultsMean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17–2.25; p=0.004) and first cardiovascular event (1.60; 1.23–2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18–1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05–3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12–2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.ConclusionsFree levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.

The Hemodialysis (HEMO) Study showed that high-dose hemodialysis providing a single-pool Kt/V of 1.71 provided no benefit over a standard treatment providing a single-pool Kt/V of 1.32. Here, we assessed whether the high-dose treatment used lowered plasma levels of small uremic solutes other than urea. Measurements made ≥3 months after randomization in 1281 patients in the HEMO Study showed a range in the effect of high-dose treatment compared with that of standard treatment: from no reduction in the level of p-cresol sulfate or asymmetric dimethylarginine to significant reductions in the levels of trimethylamine oxide (-9%; 95% confidence interval [95% CI], -2% to -15%), indoxyl sulfate (-11%; 95% CI, -6% to -15%), and methylguanidine (-22%; 95% CI, -18% to -27%). Levels of three other small solutes also decreased slightly; the level of urea decreased 9%. All-cause mortality did not significantly relate to the level of any of the solutes measured. Modeling indicated that the intermittency of treatment along with the presence of nondialytic clearance and/or increased solute production accounted for the limited reduction in solute levels with the higher Kt/V In conclusion, failure to achieve greater reductions in solute levels may explain the failure of high Kt/V treatment to improve outcomes in the HEMO Study. Furthermore, levels of the nonurea solutes varied widely among patients in the HEMO Study, and achieved Kt/V accounted for very little of this variation. These results further suggest that an index only on the basis of urea does not provide a sufficient measure of dialysis adequacy.

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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Objectives Traditional mental health services are not used by a majority of older adults with depression, suggesting a need for new methods of health service delivery. We conducted a pilot study using peer mentors to deliver depression care to older adults in collaboration with a mental health professional. We evaluated the acceptability of peer mentors to older adults and examined patient experiences of the intervention. Methods Six peer mentors met 30 patients for 1 hour weekly for 8 weeks. A mental health professional provided an initial clinical evaluation as well as supervision and guidance to peer mentors concurrent with patient meetings. We measured depressive symptoms at baseline and after study completion, and depressive symptoms and working alliance at weekly peer-patient meetings. We also interviewed participants and peer mentors to assess their experiences of the intervention. Results Ninety-six percent of patients attended all eight meetings with the peer mentor and PHQ-9 scores decreased for 85% of patients. Patients formed strong, trusting relationships with peer mentors. Patients emphasized the importance of trust, of developing a strong relationship, and of the credibility and communication skills of the peer mentor. Participants described benefits such as feeling hopeful, and reported changes in attitude, behavior, and insight. Conclusions Use of peer mentors working in collaboration with a mental health professional is promising as a model of depression care delivery for older adults. Testing of effectiveness is needed and processes of recruitment, role definition, and supervision should be further developed.

Background Asymmetric and symmetric dimethylarginines (ADMA and SDMA) are putative uremic toxins that may exert toxicity by a number of mechanisms including impaired nitric oxide synthesis and generation of reactive oxygen species. The study goal was to determine the association between these metabolites and cardiovascular outcomes in hemodialysis patients. Study Design Post hoc analysis of the Hemodialysis (HEMO) Study. Setting & Participants 1,276 prevalent hemodialysis patients with available samples 3–6 months after randomization. Predictor ADMA and SDMA measured in stored specimens. Outcomes Cardiac death, sudden cardiac death, first cardiovascular event, and any-cause death. Association with predictors analyzed using Cox regression adjusted for potential confounders (including demographics, clinical characteristics, comorbidities, albumin, and residual kidney function). Results Mean age of patients was 57 ±14 (SD) years, 63% were Black and 57% were female. Mean ADMA (0.9 ± 0.2 µM) and SDMA (4.3 ± 1.4 µM) were moderately correlated (r=0.418). Higher dialysis dose or longer session length were not associated with lower predialysis concentrations of ADMA or SDMA. In fully adjusted models, each doubling of ADMA was associated with higher risk (HR per 2-fold higher concentration; 95% CI) of cardiac death (1.83; 1.29–2.58), sudden cardiac death (1.79; 1.19–2.69), first cardiovascular event (1.50; 1.20–1.87), and any-cause death (1.44; 1.13–1.83). Compared to the lowest ADMA quintile (≤0.745 µM), the highest ADMA quintile (≥1.07 µM) was associated with higher risk (HR; 95% CI) of cardiac death (2.10; 1.44–3.05), sudden cardiac death (2.06; 1.46–2.90), first cardiovascular event (1.75; 1.35–2.27), and any-cause death (1.56; 1.21–2.00). SDMA was associated with higher risk of cardiac death (1.40; 1.03–1.92) but this was no longer statistically significant after adjusting for ADMA (1.20; 0.86–1.68). Limitations Single time-point measurement of ADMA and SDMA. Conclusions ADMA and, to a lesser extent SDMA are associated with cardiovascular outcomes in hemodialysis patients.