The effect of increased frequency of hemodialysis on vitamin C concentrations: an ancillary study of the randomized Frequent Hemodialysis Network (FHN) daily trial.

BACKGROUND: Reports on vitamin C in HD patients have shown effects of vitamin C deficiency in association with scurvy symptoms. Dialyzability of water soluble vitamins is high, and substantial losses in those who are dialyzed more frequently were hypothesized. The randomized FHN Daily Trial compared the effects of in-center HD six versus three times per week. We studied baseline correlations between vitamin C and potentially associated parameters, and the effect of more frequent HD on circulating vitamin C concentrations. METHODS: We studied vitamin C levels at baseline and months, 3, 5 and 11. Patients enrolled between 2007 and 2009 into the randomized FHN Daily trial in the East Coast consortium were approached for participation. Predialysis plasma samples were processed with metaphosphoric acid and frozen at - 70 °C for measurement with HPLC. Regression models between baseline log-transformed vitamin C and hemoglobin, CRP, eKt/V, ePCR and PTH, and a linear mixed-effects model to estimate the effect size of more frequent HD on plasma vitamin C, were constructed. RESULTS: We studied 44 subjects enrolled in the FHN Daily trial (50 ± 12 years, 36% female, 29% Hispanics and 64% blacks, 60% anuric). Vitamin C correlated significantly with predialysis hemoglobin (r = 0.3; P = 0.03) and PTH (r = - 0.3, P = 0.04), respectively. Vitamin C did not significantly differ at baseline (6×/week, 25.8 ± 25.9 versus 3×/week, 32.6 ± 39.4 µmol/L) and no significant treatment effect on plasma vitamin C concentrations was found [- 26.2 (95%CI -57.5 to 5.1) µmol/L at Month 4 and - 2.5 (95%CI -15.6 to 10.6) µmol/L at Month 12. CONCLUSIONS: Based on data from this large randomized-controlled trial no significant effect of the intervention on circulating plasma vitamin C concentrations was found, allaying the concerns that more frequent HD would affect the concentrations of water-soluble vitamins and adversely affect patient's well-being. Correlations between vitamin C and hemoglobin and PTH support the importance of vitamin C for normal bone and mineral metabolism, and anemia management.

Intensive Hemodialysis, Mineral and Bone Disorder, and Phosphate Binder Use.

Mineral and bone disorder is a common complication of end-stage renal disease. Notably, hyperphosphatemia likely promotes calcification of the myocardium, valves, and arteries. Hyperphosphatemia is associated with higher risk for cardiovascular mortality and morbidity along a gradient beginning at 5.0mg/dL. Among contemporary hemodialysis (HD) patients, mean serum phosphorus level is 5.2mg/dL, although 25% of patients have serum phosphorus levels of 5.5 to 6.9mg/dL; and 13%, >7.0mg/dL. Treatment of hyperphosphatemia is burdensome. Dialysis patients consume a mean of 19 pills per day, half of which are phosphate binders. Medicare Part D expenditures on binders for dialysis patients approached $700 million in 2013. Phosphorus removal with thrice-weekly HD (4 hours per session) is ∼3,000mg/wk. However, clearance is unlikely to counterbalance dietary intake, which varies around a mean of 7,000mg/wk. Dietary restriction and phosphate binders are important interventions, but each has limitations. Dietary control is complicated by limited access to healthy food choices and unclear labeling. Meanwhile, adherence to phosphate binders is poor, especially in younger patients and those with high pill burden. Multiple randomized clinical trials show that intensive HD reduces serum phosphorus levels. In the Frequent Hemodialysis Network (FHN) trial, short daily and nocturnal schedules reduced serum phosphorus levels by 0.6 and 1.6mg/dL, respectively, relative to 3 sessions per week. A similar effect of nocturnal HD was observed in an earlier trial. In the daily arm of the FHN trial, intensive HD significantly lowered estimated phosphate binder dose per day, whereas in the nocturnal arm, intensive HD led to binder discontinuation in 75% of patients. However, intensive HD appears to have no meaningful effects on serum calcium and parathyroid hormone concentrations. In conclusion, intensive HD, especially nocturnal HD, lowers serum phosphorus levels and decreases the need for phosphate binders.

Intensive Hemodialysis, Blood Pressure, and Antihypertensive Medication Use.

Hypertension is a cardinal feature of end-stage renal disease (ESRD). Hypertensive nephropathy is the primary cause of ESRD for nearly 30% of patients, and the prevalence of hypertension is >85% in new patients with ESRD. In contemporary hemodialysis (HD) patients, mean predialysis systolic blood pressure (SBP) is nearly 150mmHg, and about 70%, 50%, and 40% use ß-blockers, calcium channel blockers, and renin-angiotensin system inhibitors, respectively. Predialysis SBP generally exhibits a U-shaped association with mortality risk. Interdialytic ambulatory SBP is more strongly associated with risk. Hypertension is multifactorial; key causes include persistent hypervolemia and elevated peripheral resistance. With 3 HD sessions per week, blood pressure (BP) climbs during the interdialytic interval, in step with interdialytic weight gain, particularly among elderly patients and those with higher dry weight. Elevated peripheral resistance can be attributed to inappropriate activation of the sympathetic nervous system due to higher plasma norepinephrine concentrations. Multiple randomized clinical trials show that intensive HD reduces BP and the need for oral medications indicated for hypertension. In the first 2 months of the Frequent Hemodialysis Network trial, the short daily schedule reduced predialysis SBP by 7.7mmHg, whereas the nocturnal schedule reduced predialysis SBP by 7.3mmHg, both relative to 3 sessions per week. Improvements were sustained after 12 months. Both schedules reduced antihypertensive medication use relative to 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, the mean number of prescribed antihypertensive agents decreased from 1.7 to 1.0 in 1 year, whereas the percentage of patients not prescribed antihypertensive agents increased from 21% to 47%. Nocturnal HD appears to markedly reduce total peripheral resistance and plasma norepinephrine and restore endothelium-dependent vasodilation. In conclusion, intensive HD reduces BP and the need for antihypertensive medications.

Intensive Hemodialysis and Health-Related Quality of Life.

Diminished health-related quality of life (HRQoL) is common in dialysis patients and associated with increased risks for morbidity and mortality. Patients may present limitations in both physical and mental HRQoL. Poor physical HRQoL may be defined by limited physical function, role limitations due to physical health, dissatisfaction with physical ability, and impaired mobility. Sleep disorders such as obstructive sleep apnea, restless legs, and fatigue are typical manifestations of poor physical HRQoL in dialysis patients. Poor mental HRQoL may be defined by depressive thinking, lack of positive affect, anxiety, and feelings of social isolation. The prevalence of depression is high in dialysis patients. Intensive hemodialysis (HD) can positively address HRQoL. In 3 randomized clinical trials, relative to conventional HD, intensive HD increased physical and mental component summary scores from the 36-Item Short-Form Health Survey (SF-36), although individual treatment effects of daily nocturnal HD were not statistically significant. In another large prospective study, initiation of short daily HD therapy was followed after 12 months by improvements in all SF-36 domains, sleep quality, and restless legs symptoms. In a small study of nocturnal HD, apnea and hypopnea episodes per hour decreased by almost 70% after conversion from conventional HD. Intensive HD is also associated with a large reduction in postdialysis recovery time. In contrast, 2 randomized clinical trials failed to demonstrate statistically significant effects of intensive HD on the Beck Depression Inventory score despite a significant decrease in Beck Depression Inventory score in the prospective study of short daily HD. Furthermore, intensive HD may not improve objective physical performance and can increase burden on caregivers in the home setting. In conclusion, intensive HD potentially can address both physical and mental aspects of poor HRQoL relative to conventional HD. However, more studies are needed to understand the effects of intensive HD, including specific schedules, on HRQoL.

Intensive Hemodialysis and Treatment Complications and Tolerability.

Hemodialysis (HD) treatment can be difficult to tolerate. Common complications are intradialytic hypotension (IDH) and long time to recovery after an HD session. IDH, as defined by nadir systolic blood pressure < 90mmHg and intradialytic decline > 30mmHg, occurs in almost 8% of HD sessions. IDH may be caused by aggressive ultrafiltration in response to interdialytic weight gain, can lead to myocardial stunning and cardiac arrhythmias, and is associated with increased risk for death. Long recovery time after a treatment session is also common. In DOPPS (Dialysis Outcomes and Practice Patterns Study), recovery time was 2 to 6 hours for 41% of HD patients and longer than 6 hours for 27%; recovery time was linearly associated with increased risks for death and hospitalization. Importantly, both decreases in blood pressure and feeling washed out or drained have been identified by patients as more important outcomes than death or hospitalization. Intensive HD likely reduces the likelihood of IDH. In the Frequent Hemodialysis Network trial, short daily and nocturnal schedules reduced the per-session probability of IDH by 20% and 68%, respectively, relative to 3 sessions per week. Due to lower ultrafiltration volume and/or rate, intensive HD may reduce intradialytic blood pressure variability. In a cross-sectional study, short daily and nocturnal schedules were associated with slower ultrafiltration and less dialysis-induced myocardial stunning than 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, recovery time was reduced after 12 months from 8 hours to 1 hour, according to per-protocol analysis. Recovery time after nocturnal HD may be minutes. In conclusion, intensive HD can improve the tolerability of HD treatment by reducing the risk for IDH and decreasing recovery time after HD. These changes may improve the patient centeredness of end-stage renal disease care.

Intensive Hemodialysis, Left Ventricular Hypertrophy, and Cardiovascular Disease.

The prevalence of cardiovascular disease, including cardiac arrhythmia, coronary artery disease, cardiomyopathy, and valvular heart disease, is higher in hemodialysis (HD) patients than in the US resident population. Cardiovascular disease is the leading cause of death in HD patients and the principal discharge diagnosis accompanying 1 in 4 hospital admissions. Furthermore, the rate of hospital admissions for either heart failure or fluid overload is persistently high despite widespread use of ß-blockers and renin-angiotensin system inhibitors and attempts to manage fluid overload with ultrafiltration. An important predictor of cardiovascular mortality and morbidity in dialysis patients is left ventricular hypertrophy (LVH). LVH is an adaptive response to increased cardiac work, typically caused by combined pressure and volume overload, resulting in cardiomyocyte hypertrophy and increased intercellular matrix. In new dialysis patients, the prevalence of LVH is 75%. Regression of LVH may reduce cardiovascular risk, including the incidence of heart failure, complications after myocardial infarction, and sudden arrhythmic death. Multiple randomized clinical trials show that intensive HD reduces left ventricular mass, a measure of LVH. Short daily and nocturnal schedules in the Frequent Hemodialysis Network trial reduced left ventricular mass by 14 (10%) and 11 (8%) g, respectively, relative to 3 sessions per week. Comparable efficacy was observed in an earlier trial of nocturnal HD. Intensive HD also improves cardiac rhythm. Clinical benefits have been reported only in observational studies. Daily home HD is associated with 17% and 16% lower risks for cardiovascular death and hospitalization, respectively; admissions for cerebrovascular disease, heart failure, and hypertensive disease, which collectively constitute around half of cardiovascular hospitalizations, were less likely with daily home HD. Relative to peritoneal dialysis, daily home HD is likewise associated with lower risk for cardiovascular hospitalization. In conclusion, intensive HD likely reduces left ventricular mass and may lead to lower risks for adverse cardiac events.

Intensive Hemodialysis and Potential Risks With Increasing Treatment.

Although intensive hemodialysis (HD) can address important clinical problems, increasing treatment also introduces risks. In this review, we assess risks pertaining to 6 domains: vascular access complications, infection, mortality, loss of residual kidney function, solute balance, and patient and care partner burden. In the Frequent Hemodialysis Network (FHN) trials, short daily and nocturnal schedules increased the incidence of access complications, although the incidence of access loss was not statistically higher. Observational studies indicate that infection-related hospitalization is an ongoing challenge with short daily HD. Excess risk may be catalyzed by poor infection control practices in the home setting in which intensive HD is typically delivered, but with fixed probability of bacterial contamination per cannulation, greater treatment frequency necessarily increases the risk for infectious complications. Buttonhole cannulation may increase the risk for metastatic infections. However, intensive HD in the home setting is associated with lower risk for infection than peritoneal dialysis. Data regarding mortality are equivocal. With extended follow-up of individuals in the FHN trials, short daily HD was associated with lower risk relative to the usual schedule, whereas nocturnal HD was associated with higher risk. In many, but not all, observational studies, short daily HD has been associated with lower risk than both in-center HD and peritoneal dialysis; however, observational studies are subject to unmeasured confounding. Intensive HD can accelerate the loss of residual kidney function in new dialysis patients with substantial urine output and can deplete solutes (eg, phosphorus) to the extent that supplementation is necessary. Finally, intensive HD may increase burden on patients and caregivers, possibly leading to technique failure. Some of these problems might be addressed with careful monitoring, so that relevant interventions (eg, antibiotics, retraining, and respite care) can be delivered. Ultimately, intensive HD is not a panacea for end-stage renal disease. Potential benefits and risks of treatment should be jointly considered.

Long-term Effects of Frequent Nocturnal Hemodialysis on Mortality: The Frequent Hemodialysis Network (FHN) Nocturnal Trial.

BACKGROUND: Few data are available regarding the long-term mortality rate for patients receiving nocturnal home hemodialysis. STUDY DESIGN: Posttrial observational study. SETTING & PARTICIPANTS: Frequent Hemodialysis Network (FHN) Nocturnal Trial participants who consented to extended follow-up. INTERVENTION: The FHN Nocturnal Trial randomly assigned 87 individuals to 6-times-weekly home nocturnal hemodialysis or 3-times-weekly hemodialysis for 1 year. Patients were enrolled starting in March 2006 and follow-up was completed by May 2010. After the 1-year trial concluded, FHN Nocturnal participants were free to modify their hemodialysis prescription. OUTCOMES & MEASUREMENTS: We obtained dates of death and kidney transplantation through July 2011 using linkage to the US Renal Data System and queries of study centers. We used log-rank tests and Cox regression to relate mortality to the initial randomization assignment. RESULTS: Median follow-up for the trial and posttrial observational period was 3.7 years. In the nocturnal arm, there were 2 deaths during the 12-month trial period and an additional 12 deaths during the extended follow-up. In the conventional arm, the numbers of deaths were 1 and 4, respectively. In the nocturnal dialysis group, the overall mortality HR was 3.88 (95% CI, 1.27-11.79; P=0.01). Using as-treated analysis with a 12-month running treatment average, the HR for mortality was 3.06 (95% CI, 1.11-8.43; P=0.03). Six-month running treatment data analysis showed an HR of 1.12 (95% CI, 0.44-3.22; P=0.7). LIMITATIONS: These results should be interpreted cautiously due to a surprisingly low (0.03 deaths/patient-year) mortality rate for individuals randomly assigned to conventional home hemodialysis, low statistical power for the mortality comparison due to the small sample size, and the high rate of hemodialysis prescription changes. CONCLUSIONS: Patients randomly assigned to nocturnal hemodialysis had a higher mortality rate than those randomly assigned to conventional dialysis. The implications of this result require further investigation.

Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial.

BACKGROUND: End-stage renal disease is associated with reduced heart rate variability (HRV), components of which generally are associated with advanced age, diabetes mellitus and left ventricular hypertrophy. We hypothesized that daily in-center hemodialysis (HD) would increase HRV. METHODS: The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to receive 12 months of six versus three times per week in-center HD. Two hundred and seven patients had baseline Holter recordings. HRV measures were calculated from 24-h Holter electrocardiograms at both baseline and 12 months in 131 patients and included low-frequency power (LF, a measure of sympathetic modulation), high-frequency power (HF, a measure of parasympathetic modulation) and standard deviation (SD) of the R-R interval (SDNN, a measure of beat-to-beat variation). RESULTS: Baseline to Month 12 change in LF was augmented by 50% [95% confidence interval (95% CI) 6.1-112%, P =0.022] and LF + HF was augmented by 40% (95% CI 3.3-88.4%, P = 0.03) in patients assigned to daily hemodialysis (DHD) compared with conventional HD. Changes in HF and SDNN were similar between the randomized groups. The effects of DHD on LF were attenuated by advanced age and diabetes mellitus (predefined subgroups). Changes in HF (r = -0.20, P = 0.02) and SDNN (r = -0.18, P = 0.04) were inversely associated with changes in left ventricular mass (LVM). CONCLUSIONS: DHD increased the LF component of HRV. Reduction of LVM by DHD was associated with increased vagal modulation of heart rate (HF) and with increased beat-to-beat heart rate variation (SDNN), suggesting an important functional correlate to the structural effects of DHD on the heart in uremia.