Treating Home Versus Predialysis Blood Pressure Among In-Center Hemodialysis Patients: A Pilot Randomized Trial.

RATIONALE & OBJECTIVE: Observational studies have reported a U-shaped association between blood pressure (BP) before a hemodialysis session and death. In contrast, because a linear association between out-of-dialysis-unit BP and death has been reported, home BP may be a better target for treatment. To test the feasibility of this approach, we conducted a pilot trial of treating home versus predialysis BP in hemodialysis patients. STUDY DESIGN: A 4-month, parallel, randomized, controlled trial. SETTINGS & PARTICIPANTS: 50 prevalent hemodialysis patients in San Francisco and Seattle. Participants were randomly assigned using 1:1 block randomization, stratified by site. INTERVENTIONS: To target home systolic BP (SBP) of 100-<140 mm Hg versus predialysis SBP of 100-<140mm Hg. Home and predialysis SBPs were ascertained every 2 weeks. Dry weight and BP medications were adjusted to reach the target SBP. OUTCOMES: Primary outcomes were feasibility, adherence, safety. and tolerability. RESULTS: 50 of 70 (71%) patients who were approached agreed to participate. All enrollees completed the study except for 1 who received a kidney transplant. In the home BP treatment group, adherence to obtaining/reporting home BP was 97.4% (and consistent over the 4 months). There was no increased frequency of high (defined as SBP>200mm Hg; 0.2% vs 0%) or low (defined as<90mm Hg; 1.8% vs 1.2%) predialysis BP readings in the home versus predialysis treatment arms, respectively. However, participants in the home BP arm had higher frequency of fatigue (32% vs 16%). LIMITATIONS: Small sample size. CONCLUSIONS: This pilot trial demonstrates feasibility and high adherence to home BP measurement and treatment in hemodialysis patients. Larger trials to test the long-term feasibility, efficacy, and safety of home BP treatment in hemodialysis patients should be conducted. FUNDERS: National Institutes of Health, Satellite Healthcare, and Northwest Kidney Centers. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03459807.

Effect of Coenzyme Q10 on Biomarkers of Oxidative Stress and Cardiac Function in Hemodialysis Patients: The CoQ10 Biomarker Trial.

BACKGROUND: Oxidative stress is highly prevalent in patients with end-stage renal disease and is linked to excess cardiovascular risk. Identifying therapies that reduce oxidative stress has the potential to improve cardiovascular outcomes in patients undergoing maintenance dialysis. STUDY DESIGN: Placebo-controlled, 3-arm, double-blind, randomized, clinical trial. SETTING & PARTICIPANTS: 65 patients undergoing thrice-weekly maintenance hemodialysis. INTERVENTION: Patients were randomly assigned in a 1:1:1 ratio to receive once-daily coenzyme Q10 (CoQ10; 600 or 1,200mg) or matching placebo for 4 months. OUTCOMES: The primary outcome was plasma oxidative stress, defined as plasma concentration of F2-isoprotanes. Secondary outcomes included levels of plasma isofurans, levels of cardiac biomarkers, predialysis blood pressure, and safety/tolerability. MEASUREMENTS: F2-isoprostanes and isofurans were measured as plasma markers of oxidative stress, and N-terminal pro-brain natriuretic peptide and troponin T were measured as cardiac biomarkers at baseline and 1, 2, and 4 months. RESULTS: Of 80 randomly assigned patients, 15 were excluded due to not completing at least 1 postbaseline study visit and 65 were included in the primary intention-to-treat analysis. No treatment-related major adverse events occurred. Daily treatment with 1,200mg, but not 600mg, of CoQ10 significantly reduced plasma F2-isoprostanes concentrations at 4 months compared to placebo (adjusted mean changes of -10.7 [95% CI, -7.1 to -14.3] pg/mL [P<0.001] and -8.3 [95% CI, -5.5 to -11.0] pg/mL [P=0.1], respectively). There were no significant effects of CoQ10 treatment on levels of plasma isofurans, cardiac biomarkers, or predialysis blood pressures. LIMITATIONS: Study not powered to detect small treatment effects; difference in baseline characteristics among randomized groups. CONCLUSIONS: In patients undergoing maintenance hemodialysis, daily supplementation with 1,200mg of CoQ10 is safe and results in a reduction in plasma concentrations of F2-isoprostanes, a marker of oxidative stress. Future studies are needed to determine whether CoQ10 supplementation improves clinical outcomes for patients undergoing maintenance hemodialysis.

Coenzyme Q10 dose-escalation study in hemodialysis patients: safety, tolerability, and effect on oxidative stress.

BACKGROUND: Coenzyme Q10 (CoQ10) supplementation improves mitochondrial coupling of respiration to oxidative phosphorylation, decreases superoxide production in endothelial cells, and may improve functional cardiac capacity in patients with congestive heart failure. There are no studies evaluating the safety, tolerability and efficacy of varying doses of CoQ10 in chronic hemodialysis patients, a population subject to increased oxidative stress. METHODS: We performed a dose escalation study to test the hypothesis that CoQ10 therapy is safe, well-tolerated, and improves biomarkers of oxidative stress in patients receiving hemodialysis therapy. Plasma concentrations of F2-isoprostanes and isofurans were measured to assess systemic oxidative stress and plasma CoQ10 concentrations were measured to determine dose, concentration and response relationships. RESULTS: Fifteen of the 20 subjects completed the entire dose escalation sequence. Mean CoQ10 levels increased in a linear fashion from 704 ± 286 ng/mL at baseline to 4033 ± 1637 ng/mL, and plasma isofuran concentrations decreased from 141 ± 67.5 pg/mL at baseline to 72.2 ± 37.5 pg/mL at the completion of the study (P = 0.003 vs. baseline and P < 0.001 for the effect of dose escalation on isofurans). Plasma F2-isoprostane concentrations did not change during the study. CONCLUSIONS: CoQ10 supplementation at doses as high as 1800 mg per day was safe in all subjects and well-tolerated in most. Short-term daily CoQ10 supplementation decreased plasma isofuran concentrations in a dose dependent manner. CoQ10 supplementation may improve mitochondrial function and decrease oxidative stress in patients receiving hemodialysis. TRIAL REGISTRATION: This clinical trial was registered on clinicaltrials.gov [NCT00908297] on May 21, 2009.

A pilot randomized crossover trial assessing the safety and short-term effects of pomegranate supplementation in hemodialysis patients.

OBJECTIVE: Oxidative stress and systemic inflammation are highly prevalent in patients undergoing maintenance hemodialysis (MHD) and are linked to excess cardiovascular risk. This study examined whether short-term supplementation with pomegranate juice and extract is safe and well tolerated by MHD patients. The secondary aim was to assess the effect of pomegranate supplementation on oxidative stress, systemic inflammation, monocyte function, and blood pressure. DESIGN: Prospective, randomized, crossover, pilot clinical trial (NCT01562340). SETTING: The study was conducted from March to October 2012 in outpatient dialysis facilities in the Seattle metropolitan area. SUBJECTS: Twenty-four patients undergoing MHD (men, 64%; mean age, 61 ± 14 years) were randomly assigned to receive pomegranate juice or extract during a 4-week intervention period. After a washout period, all patients received the alternative treatment during a second 4-week intervention period. INTERVENTION: Patients assigned to receive pomegranate juice received 100 mL of juice before each dialysis session. Patients assigned to receive pomegranate extract were given 1,050 mg of extract daily. MAIN OUTCOME MEASURES: The main outcome measures were safety and tolerability of pomegranate juice and extract. Additional secondary outcomes assessed included serum lipids, laboratory biomarkers of inflammation (C-reactive protein and interleukin 6) and oxidative stress (plasma F2 isoprostanes and isofurans), monocyte cytokine production, and predialysis blood pressure. RESULTS: Both pomegranate juice and extract were safe and well tolerated by study participants. Over the study period, neither treatment had a significant effect on lipid profiles, plasma C-reactive protein, interleukin 6, F2-isoprostane or isofuran concentrations, predialysis systolic or diastolic blood pressure nor changed the levels of monocyte cytokine production. CONCLUSIONS: Both pomegranate juice and extract are safe and well tolerated by patients undergoing MHD but do not influence markers of inflammation or oxidative stress nor affect predialysis blood pressure.

Effects of beta-blocker use on volume status in hemodialysis patients.

BACKGROUND: Removal and control of excess fluid with dialysis is considered critical for protection against cardiovascular sequelae. Antihypertensive agents including beta-blockers may influence hemodynamics, which may limit fluid removal during hemodialysis (HD). METHODS: Fifty chronic HD patients underwent bioimpedance measurement before and after a midweek dialysis session. Data on volume status, blood pressure, antihypertensive medications, and bioimpedance were analyzed. RESULTS: Patients in the high-volume status group used a significantly higher percentage of beta-blockers than patients in the low-volume status group (54.2 vs. 19.2%, respectively, p = 0.01). Multivariable regression revealed that the use of beta-blockers was independently positively associated with fluid overload (p < 0.05). Intradialytic muscle cramping occurred more often in the beta-blocker group than the control group (44.4 vs. 12.5%, respectively, p = 0.02). CONCLUSIONS: Our results suggest that the use of beta-blockers was associated with fluid overload in HD patients, and patients being treated with them experienced more intradialytic muscle cramping during dialysis.

A wearable artificial kidney for patients with end-stage renal disease.

BACKGROUND: Stationary hemodialysis machines hinder mobility and limit activities of daily life during dialysis treatments. New hemodialysis technologies are needed to improve patient autonomy and enhance quality of life. METHODS: We conducted a FDA-approved human trial of a wearable artificial kidney, a miniaturized, wearable hemodialysis machine, based on dialysate-regenerating sorbent technology. We aimed to determine the efficacy of the wearable artificial kidney in achieving solute, electrolyte, and volume homeostasis in up to 10 subjects over 24 hours. RESULTS: During the study, all subjects remained hemodynamically stable, and there were no serious adverse events. Serum electrolytes and hemoglobin remained stable over the treatment period for all subjects. Fluid removal was consistent with prescribed ultrafiltration rates. Mean blood flow was 42 ± 24 ml/min, and mean dialysate flow was 43 ± 20 ml/min. Mean urea, creatinine, and phosphorus clearances over 24 hours were 17 ± 10, 16 ± 8, and 15 ± 9 ml/min, respectively. Mean ß2-microglobulin clearance was 5 ± 4 ml/min. Of 7 enrolled subjects, 5 completed the planned 24 hours of study treatment. The trial was stopped after the seventh subject due to device-related technical problems, including excessive carbon dioxide bubbles in the dialysate circuit and variable blood and dialysate flows. CONCLUSION: Treatment with the wearable artificial kidney was well tolerated and resulted in effective uremic solute clearance and maintenance of electrolyte and fluid homeostasis. These results serve as proof of concept that, after redesign to overcome observed technical problems, a wearable artificial kidney can be developed as a viable novel alternative dialysis technology. TRIAL REGISTRATION: ClinicalTrials.gov NCT02280005. FUNDING: The Wearable Artificial Kidney Foundation and Blood Purification Technologies Inc.

Rationale and design of A Trial of Sertraline vs. Cognitive Behavioral Therapy for End-stage Renal Disease Patients with Depression (ASCEND).

Major Depressive Disorder (MDD) is highly prevalent in patients with End Stage Renal Disease (ESRD) treated with maintenance hemodialysis (HD). Despite the high prevalence and robust data demonstrating an independent association between depression and poor clinical and patient-reported outcomes, MDD is under-treated when identified in such patients. This may in part be due to the paucity of evidence confirming the safety and efficacy of treatments for depression in this population. It is also unclear whether HD patients are interested in receiving treatment for depression. ASCEND (Clinical Trials Identifier Number NCT02358343), A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression, was designed as a multi-center, 12-week, open-label, randomized, controlled trial of prevalent HD patients with comorbid MDD or dysthymia. It will compare (1) a single Engagement Interview vs. a control visit for the probability of initiating treatment for comorbid depression in up to 400 patients; and (2) individual chair-side CBT vs. flexible-dose treatment with a selective serotonin reuptake inhibitor, sertraline, for improvement of depressive symptoms in 180 of the up to 400 patients. The evolution of depressive symptoms will also be examined in a prospective longitudinal cohort of 90 HD patients who choose not to be treated for depression. We discuss the rationale and design of ASCEND, the first large-scale randomized controlled trial evaluating efficacy of non-pharmacologic vs. pharmacologic treatment of depression in HD patients for patient-centered outcomes.