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1.  Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial 
…we are starting to acknowledge the ability of modified dialysis procedures (in particular extended dialysis schedules) over the current conventional norms of frequency and duration to provide a range of benefits cutting across the range of relevant domains…”
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.
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).
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).
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.
PMCID: PMC3888308  PMID: 24078335
daily hemodialysis; end-stage renal disease; frequent hemodialysis network; heart rate variability; left ventricular mass
2.  Inflammation and Inverse Associations of Body Mass Index and Serum Creatinine With Mortality in Hemodialysis Patients 
Protein-energy wasting and inflammation are common and associated with an increased risk of mortality in hemodialysis (HD) patients. We examined the extent to which they mediate the associations of each other with death in this population.
Study Design
Retrospective analysis of the Hemodialysis (HEMO) Study data.
Prevalent HD patients.
One-thousand HEMO study participants with data available on C-reactive protein (CRP), body mass index (BMI), and serum creatinine.
Main Outcome Measure
The associations of CRP, BMI, and serum creatinine with time to all-cause mortality separately and together in multivariate Cox models.
In 1,437 patient-years of follow-up, there were 265 (26.5%) all-cause deaths. Compared with the lowest CRP quartile, the highest quartile was associated with a hazard ratio (HR) of 2.02 (95% confidence interval [CI], 1.31–3.10) for all-cause mortality. This association of highest CRP quartile with mortality was not attenuated with further adjustment for BMI and serum creatinine (HR, 2.13; 95% CI, 1.38–3.30). When serum albumin was added to the model, the hazard of death associated with highest CRP quartile was modestly attenuated (HR, 1.88; 95% CI, 1.21–2.92). In contrast, both BMI (for each kg/m2 increase; HR, 0.94; 95% CI, 0.91–0.96 for all-cause mortality) and serum creatinine (for each mg/dL increase; HR, 0.85; 95% CI, 0.79–0.90 for all-cause mortality) had strong, independent protective effects. Further adjustment with CRP had a negligible effect on these associations.
The associations of markers of nutrition and inflammation with mortality are largely independent of each other in HD patients.
PMCID: PMC4265765  PMID: 17971309
3.  Impact of frequent hemodialysis on anemia management: results from the Frequent Hemodialysis Network (FHN) Trials 
Nephrology Dialysis Transplantation  2013;28(7):1888-1898.
The extent to which anemia management is facilitated by more frequent hemodialysis (HD) is controversial. We hypothesized as a preselected outcome that patients receiving HD six times (6×) compared with three times (3×) per week would require lower doses of erythropoietin-stimulating agents (ESA) and/or achieve higher blood hemoglobin (Hb) concentrations.
Subjects enrolled in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials were studied. As the primary outcome for anemia, the dose of ESAs was recorded at 4-month intervals and the monthly dose of intravenous iron (IV Fe) was reported. Serum iron, transferrin saturation and ferritin were measured at baseline and then at 4-month intervals, whereas Hb concentration was measured monthly.
There was no significant treatment effect in the 6× versus 3× treatment groups on logESA dose or the ratio of log of ESA dose to Hb concentration in either trial. In the daily trial, Hb concentrations increased significantly in the 6× versus 3× group, at Month 12 compared with baseline (0.3 g/dL; 95% CI: 0.05–0.58, P < 0.021), but both groups had Hb concentrations in the usual target range. In the daily trial, the weekly logESA dose and the logESA dose to Hb concentration ratio tended to decline more in the 6× versus 3× group. This trend was not observed in the nocturnal trial. IV Fe doses were significantly lower in the 6× compared with the 3× group by Month 12 in the nocturnal trial, but not different in the daily trial.
In the FHN Daily and Nocturnal Trials, more frequent HD did not have a significant or clinically important effect on anemia management.
PMCID: PMC3707527  PMID: 23358899
anemia; erythropoietin; frequent; hemodialysis; nocturnal
4.  Effect of More Frequent Hemodialysis on Cognitive Function in the Frequent Hemodialysis Network Trials 
Cognitive impairment is common among patients with end-stage renal disease receiving hemodialysis 3x-per-week.
Study Design
Randomized Clinical Trial
Setting & Participants
218 subjects participating in the Frequent Hemodialysis Network (FHN) Daily Trial and 81 subjects participating in the FHN Nocturnal Trial.
The Daily Trial tested in-center hemodialysis 6x-per-week versus 3x-per-week. The Nocturnal Trial tested home nocturnal hemodialysis 6x-per-week versus home or in-center hemodialysis 3x-per-week.
Cognitive function was measured at baseline, month four, and month 12. The primary outcome was performance on the Trail-Making Test, Form B, a measure of executive function, and a secondary outcome was performance on the Modified Mini-Mental State Examination, a measure of global cognition. The domains of attention, psychomotor speed, memory and verbal fluency were assessed in 59 participants in the Daily Trial and 19 participants in the Nocturnal Trial.
We found no benefit of frequent hemodialysis in either trial for the primary cognitive outcome (Daily Trial: OR for improvement, 0.99; 95% CI, 0.59–1.66; Nocturnal Trial: OR, 1.19; 95% CI, 0.48–2.96). Similarly, there was no benefit of frequent hemodialysis in either trial on global cognition, the secondary cognitive outcome. Exploratory analyses in the Daily Trial suggested possible benefits of frequent hemodialysis on memory and verbal fluency, but not on attention and psychomotor speed. Exploratory analyses in the Nocturnal Trial suggested no benefit of frequent hemodialysis on attention, psychomotor speed, memory, or verbal fluency.
Unblinded intervention, small sample
Frequent hemodialysis did not improve executive function or global cognition.
PMCID: PMC3546160  PMID: 23149295
dialysis; end-stage renal disease; cognitive function
5.  Frequent nocturnal hemodialysis accelerates the decline of residual kidney function 
Kidney international  2013;83(5):10.1038/ki.2012.457.
Frequent hemodialysis can alter volume status, blood pressure and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to 6 compared to 3 times per week hemodialysis on follow up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 l/d, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared to controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared to 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 l/d, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.
PMCID: PMC3855839  PMID: 23344474
6.  Determinants of Left Ventricular Mass in Patients on Hemodialysis: the Frequent Hemodialysis Network (FHN) Trials 
An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.
Methods and Results
The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several pre-defined baseline demographic or clinical factors, as well as change in volume removal, blood pressure or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1(95% CI 5.0 to 21.3) g, p=0.002), LVM index (6.9 (2.4 to 11.3) g/m2, p=0.003) and percent change in geometric mean of LVM (7.0 (1.0 to 12.6)%, p =0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.
Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure.
PMCID: PMC3328963  PMID: 22360996
Left Ventricular Mass; Frequent Hemodialysis; Daily Hemodialysis; Nocturnal Hemodialysis; Blood Pressure
7.  The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial 
Kidney international  2011;80(10):1080-1091.
Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/Vurea, a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.
PMCID: PMC3569086  PMID: 21775973
hemodialysis; left ventricular mass; nocturnal hemodialysis; RAND physical health composite (PHC) SF-36; randomized clinical trial; vascular access
8.  The Effect of Frequent Hemodialysis on Nutrition and Body Composition: Frequent Hemodialysis Network Trial 
Kidney International  2012;82(1):90-99.
We investigated the effects of frequency of hemodialysis on nutritional status by analyzing the data in the Frequent Hemodialysis Network Trial. We compared changes in albumin, body weight and composition among 245 patients randomized to 6- or 3-times per week in-center hemodialysis (Daily Trial) and 87 patients randomized to 6-times per week nocturnal or 3-times per week conventional hemodialysis, performed largely at home (Nocturnal Trial). In the Daily Trial, there were no significant differences between groups in changes in serum albumin or the equilibrated protein catabolic rate by 12 months. There was a significant relative decrease in pre-dialysis body weight of 1.5 ± 0.2 kg in the 6 times per week group at one month, but this significantly rebounded by 1.3 ± 0.5 kg over the remaining 11 months. Extracellular water decreased in the 6 times per week compared to the 3 per week hemodialysis group. There were no significant between-group differences in phase angle, intracellular water or body cell mass. In the Nocturnal Trial, there were no significant between-group differences in any study parameter. Any gain in “dry” body weight corresponded to increased adiposity rather than muscle mass but was not statistically significant. Thus, frequent in-center hemodialysis reduced extracellular water but did not increase serum albumin or body cell mass while frequent nocturnal hemodialysis yielded no net effect on parameters of nutritional status or body composition.
PMCID: PMC3328304  PMID: 22456602
9.  Burden on caregivers as perceived by hemodialysis patients in the Frequent Hemodialysis Network (FHN) trials 
Nephrology Dialysis Transplantation  2011;26(7):2316-2322.
Background. Patients with end-stage renal disease often rely on unpaid caregivers to assist them with their daily living and medical needs. We characterized the degree to which patients enrolled in the Frequent Hemodialysis Network (FHN) trials perceived burden on their unpaid caregivers.
Methods. Participants completed the Cousineau Perceived Burden Scale, a 10-question scale previously developed in hemodialysis (HD) patients. Associations between baseline burden score and prespecified variables were evaluated using multivariable linear regression.
Results. Of 412 participants, 236 (57%) reported having unpaid caregivers. Compared to those without unpaid caregivers, these participants had greater comorbidity (Charlson mean 1.8 ± 1.8 versus 1.2 ± 1.7, P < 0.001), lower Short Form-36 (SF-36) Physical Health Composite (PHC) scores (median 33 versus 41, P < 0.001, higher Beck Depression scores (mean 16 ± 11 versus 12 ± 9, P < 0.001), and worse physical function. Median Cousineau score was 35 (interquartile range 20–53) (theoretical range 0–100). Over 50% felt their caregivers were overextended, yet 60% were confident that their caregivers could handle the demands of caring for them. Higher perceived burden was not associated with ability to be randomized. In adjusted analyses, Cousineau score was inversely associated with SF-36 PHC and Mental Health Composite scores and directly associated with Beck Depression score (each P < 0.001).
Conclusions. Most HD patients in the FHN trials perceived substantial burden on their unpaid caregivers, and self-perceived burden was associated with worse depression and quality of life. Evaluation of the effects of frequent HD on perceived burden borne by caregivers in the FHN trials will help to establish the net benefits/determents of these intensive dialytic strategies.
PMCID: PMC3716283  PMID: 21421590
burden; caregiver; depression; frequent hemodialysis; quality of life
10.  Impact of Sleep Quality on Cardiovascular Outcomes in Hemodialysis Patients: Results from the Frequent Hemodialysis Network Study 
American Journal of Nephrology  2011;33(5):398-406.
Poor sleep quality is a common, persistent, and important problem to patients with end-stage renal disease (ESRD). This report examines whether sleep quality is associated with dialysis treatment factors and other modifiable clinical factors in a large group of hemodialysis (HD) patients.
Cross-sectional analyses were conducted on baseline data collected from participants in the Frequent Hemodialysis Network trials. Sleep quality was measured using the Medical Outcomes Study Sleep Problems Index II (SPI II), a 9-item measure of sleep quality with higher scores reflecting poorer sleep quality.
The participants had an age of 51.2 ± 13.6 years, 61% were male, 38% were black, and 42% had diabetes. Higher pre-dialysis serum phosphorus (per 0.5 mg/ml) (OR 0.91; 95% CI 0.85, 0.96) and depression (OR 0.16; 95% CI 0.10, 0.25) were independently associated with decrements in sleep quality. There was also a difference in time to recovery from dialysis for the fourth versus the first SPI II quartile (5.1 h; p < 0.0001).
These findings underscore the link between sleep and daytime function and suggest that improving sleep may provide an opportunity to improve outcomes in ESRD. Whether sleep problems may be improved by reduction of serum phosphorus or treatment of depression in the HD population merits further investigation.
PMCID: PMC3080580  PMID: 21474924
Hemodialysis; Sleep; Quality of life; Cognitive function; Cardiac magnetic resonance imaging
11.  Baseline Characteristics of Participants in the Frequent Hemodialysis Network Daily and Nocturnal Trials 
The annual mortality rate for maintenance hemodialysis patients in the United States remains unacceptably high at 15–20%. In 2004, we initiated the Frequent Hemodialysis Network (FHN) clinical trials. This report presents baseline characteristics of FHN trial participants and compares them to hemodialysis patients tracked in USRDS data.
Study design
Two separate randomized clinical trials
Settings and participants
FHN includes 332 patients with chronic kidney disease requiring chronic dialysis therapy enrolled in two separate randomized clinical trials. The FHN Daily Trial (245 randomized subjects) was designed to compare outcomes of six times per week in-center daily hemodialysis (1.5 to 2.75 hours/session) with conventional three times per week in-center hemodialysis. The FHN Nocturnal Trial (87 randomized subjects) was designed to compare outcomes of six times per week nocturnal (6 to 8 hours/session) with conventional three times per week hemodialysis. USRDS data includes 338109 incident and prevalent chronic hemodialysis patients from the calendar year 2007.
Subjects in both trials were, on average, younger than the average hemodialysis patient in the United States (50.4 years; p<0.001 for Daily and 52.8 years; p<0.001 for Nocturnal). Compared to USRDS data, whites were underrepresented in the Daily Trial (36% versus 55%, p<0.001) while Hispanics were underrepresented in the Nocturnal Trial and overrepresented in the Daily Trial (0% versus 28%; p<0.001). In addition, there were more fistulas and fewer catheters in the Daily Trial (61% and 20% respectively, p<0.001 for both) and fewer grafts and more catheters in the Nocturnal Trial (10% and 44% respectively, p<0.005 for both).
Clinical trial exclusion criteria and patient willingness to participate limit comparisons with the USRDS.
FHN participants are younger and the racial composition for each study was different than the racial composition of the aggregate US dialysis population. Catheters for vascular access were more common in FHN Nocturnal participants.
PMCID: PMC3058226  PMID: 21122961
frequent hemodialysis; daily hemodialysis; nocturnal hemodialysis; left ventricular hypertrophy; physical functioning; randomized clinical trial
12.  Baseline Physical Performance, Health, and Functioning of Participants in the Frequent Hemodialysis Network (FHN) Trial 
Self-reported physical health and functioning and direct measures of physical performance are decreased in hemodialysis patients and are associated with mortality and hospitalization.
Study Design
We determined baseline cross-sectional associations of physical performance, health, and functioning with demographics, clinical characteristics, nutritional indexes, laboratory benchmarks, and measures of body composition in participants in the Frequent Hemodialysis Network (FHN) trial.
Setting & Participants
375 persons enrolled in the FHN with data for physical performance, health, and functioning.
Explanatory variables were categorized into fixed factors of age, race, comorbid conditions (diabetes mellitus, heart failure, and peripheral arterial disease) and potentially modifiable factors of dialysis dose, phosphorus level, hemoglobin level, equilibrated normalized protein catabolic rate (enPCR), body composition, body mass index, phase angle, and ratio of intracellular water volume to body weight (calculated from bioelectrical impedance).
Scores on tests of physical performance, health, and functioning.
Physical performance measured using the Short Physical Performance Battery, self-reported physical health and functioning using the 36-Item Short Form Health Survey (SF-36). Body composition (body mass index and bioimpedance analysis) and laboratory data were obtained from affiliated dialysis providers.
Relative to population norms, scores for all 3 physicality metrics were low. Poorer scores on all 3 metrics were associated with diabetes mellitus and peripheral arterial disease. Poorer scores on the SF-36 Physical Functioning subscale and Short Physical Performance Battery also were associated with age, lower ratio of intracellular water volume to body weight, and lower enPCR. Black race was associated with poorer scores on the Short Physical Performance Battery.
This was a cross-sectional study of individuals agreeing to participate in the FHN study and may not be generalizable to the general dialysis population.
Hemodialysis patients show markedly impaired physical performance, health, and functioning relative to population norms. Although some factors associated with these impairments are not modifiable, others may change with improvement in nutritional status or body composition.
PMCID: PMC3073398  PMID: 21184919
Cardiovascular disease; congestive heart failure; diabetes; inflammation; intracellular water; muscle mass; phase angle; peripheral arterial disease
13.  Folic Acid Supplementation and Cardiac and Stroke Mortality among Hemodialysis Patients 
To assess whether use of folic acid vitamin supplements reduces cardiac and stroke mortality in hemodialysis patients. Further, we examined whether consumption of folic acid from vitamin supplements greater than 1000 μg compared to standard 1000 μg, and 1000 μg compared to either lower dose or no consumption were associated with reduced cardiac and stroke mortality risk.
Secondary analysis of data from the Hemodialysis (HEMO) Study, a randomized clinical trial examining dialysis treatment regimens over three years follow-up. Participants: One thousand eight hundred and forty-six hemodialysis patients previously participating in the HEMO study.
Main Outcome Measure
Cardiac and stroke mortality.
From time-dependent Cox proportional hazard regression models, folic acid consumption from vitamin supplements, above or below the standard 1000 μg dose was not associated with decrease or increase in cardiac mortality (P = 0.53 above vs. standard dose and P = 0.46, below vs. standard dose). There was also no association between folic acid consumption and mortality from stroke (P = 0.27, above vs. standard dose and P = 0.64, below vs. standard dose).
Consumption of higher than the standard 1000 μg prescribed dose of folic acid was not beneficial in reducing cardiac or stroke mortality in hemodialysis patients. Similarly, consumption of lower than standard dose was not associated with an increase in either cardiac or stroke mortality.
PMCID: PMC2892247  PMID: 20303789
Folic acid; cardiac; stroke; mortality; hemodialysis

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