More Intensive Hemodialysis
Alan S. Kliger
Department of Medicine, Hospital of Saint Raphael and Department of Internal Medicine, Yale University School of
Medicine, New Haven, Connecticut
Clinical outcomes have not improved substantially for patients treated with conventional thrice weekly hemodialysis. More
intensive hemodialysis regimens, including daily short dialysis, and nocturnal prolonged dialysis show promise to improve
morbidity and mortality. Published studies and trials underway examining these therapies are reviewed.
Clin J Am Soc Nephrol 4: S121–S124, 2009. doi: 10.2215/CJN.02920509
D
ialysis patients have high mortality and morbidity,
despite decades of experience with renal replacement
therapy. The expected remaining lifetime for dialysis
patients is substantially lower than for the general U.S. popu-
lation. For example, a woman 40 to 44 yr old in the general
population can expect on average 40 more years of life, but if
she is on dialysis her life expectancy is only 8.1 yr (1). She is also
more likely to suffer with cardiovascular disease, anemia, sep-
ticemia, metabolic bone disease, depression, malnutrition, in-
flammation, and physical and cognitive impairment. In 1981,
the National Cooperative Dialysis Study was published, show-
ing that morbidity was related to time on dialysis and urea
removal (2). Since most hemodialysis is performed in-center
with thrice weekly treatments, it seemed logical to extend treat-
ment times and enhance urea removal to improve outcomes.
Unfortunately, HEMO, a prospective randomized controlled
trial comparing high versus low dose and high versus low flux
thrice weekly dialysis failed to show any improvement in sur-
vival for patients receiving the higher dose dialysis (3). In
retrospect, these findings are not surprising, since for small
molecules, like urea, net solute removal declines during each
dialysis session. Thus a modest increase in each dialysis session
did not result in a substantial change in dialysis dose or sur-
vival. To achieve better dialysance, it will be necessary to move
beyond thrice weekly hemodialysis to more intensive dialysis
treatments. Hemodiafiltration has shown some promise in Eu-
rope (4). This review addresses evidence that longer or more
frequent hemodialysis holds promise to improve outcomes.
Thrice Weekly Prolonged Hemodialysis
More than 25 yr ago, Charra and colleagues from Tassin,
France, first published their experience with thrice weekly long
duration, slow flow hemodialysis (5). Patients were treated
with low salt diet, long, slow dialysis and focused efforts to
return total body volume to normal. Initial and follow-up stud-
ies (6) over many years showed impressive volume control, BP
control without use of many antihypertensive medications and
remarkable survival. Despite these findings, dialysis in the
Correspondence: Dr. Alan S. Kliger, Department of Medicine, Hospital of Saint
Raphael, 1450 Chapel Street, New Haven, CT 06511. Phone: 203-789-3203; Fax:
203-789-3222; E-mail: akliger@srhs.org
Copyright © 2009 by the American Society of Nephrology
United States moved toward shorter rather than longer treat-
ments. When higher surface area dialyzers accelerated small
molecule removal, and use of urea-based measures of dialysis
adequacy became standard, hemodialysis treatments times
were reduced. Few centers in the world followed Dr. Charra’s
lead in offering prolonged dialysis treatments. In recent years,
Charra’s basic technique has been adapted to create in-center
nocturnal hemodialysis (INHD), delivering thrice weekly over-
night treatments lasting 6 to 8 h with reduced blood pump
speeds of about 300ml/min. Such prolonged dialysis allows for
more gradual ultrafiltration, an improvement in dialysis that
might be expected to improve patient survival (7). Troidle and
colleagues (8) reported results in 16 patients switched from
conventional to INHD. Kt/Vurea rose from 1.2 ⫾ 0.16 to 2.6 ⫾
0.65 and the ultrafiltration rate fell from 10.3 ⫾ 4.5 to 5.9 ⫾ 1.7
ml/h/Kg. Despite the need to spend three nights a week sleep-
ing in a dialysis facility, INHD patients had no measurable
change in psychosocial assessments. Phosphorus levels fell
from 5.3 ⫾ 1.3 to 4.4 ⫾ 1.1 mg/dl. In another study from
Toronto, Bugeja et al. switched 39 patients from conventional to
8-h INHD (9). They also found increased urea removal (urea
reduction ratio increased from 74% to 89%) and improved
phosphorus control (phosphorus fell from 5.9 to 3.7 mg/dl).
Patients required fewer antihypertensive medications to con-
trol BP, and lower doses of erythropoesis- stimulating agents to
treat anemia. Quality of life, as assessed with a ten-point Likert
scale, improved, as did sleep, intradialytic cramps, appetite and
energy level. The overnight technique did not appear to induce
fatigue or increased intrusion into daily life. Finally, at the 2008
annual meeting of the American Society of Nephrology, OK
and colleagues from Turkey described the results of 224 pa-
tients switched from conventional to 8 h INHD (10). When
compared prospectively with a matched cohort of patients on
conventional 4-h hemodialysis 3 d/wk, the INHD patients had
25% as many hospitalizations, less intradialytic hypotension,
lower phosphorus, reduced arterial stiffness and improved cog-
nitive function. Remarkably, the authors reported INHD pa-
tients had a 78% reduction in mortality. INHD has been grow-
ing rapidly in the United States: the two largest dialysis
providers reported treating more than 1600 patients with INHD
in March 2009. Dialysis providers may find INHD a particu-
ISSN: 1555-9041/401–0121
S122 Clinical Journal of the American Society of Nephrology
larly attractive way to provide more intensive dialysis — dial-
ysis centers are usually closed at night, so the marginal cost to
establish an INHD program is less than for opening conven-
tional daytime dialysis. Bujega et al. describe several barriers to
INHD, including nurse recruitment, nocturnal physician visits
and the need to accommodate comfortable sleep for patients
(9).
Daily, Short Duration Hemodialysis
Many case reports and small series of patients treated with
daily, short duration hemodialysis have been published. Suri
and colleagues published a systematic review of these reports
in 2006 (11). After screening more than 800 citations, 233 full
text articles were reviewed in detail. Only 25 of them met these
inclusion criteria: five or more adult patients, follow-up of at
least 3 mo, dialysis prescription of 1.5 to 3 h, 5 to 7 d/wk and
published after 1989. A systematic review of these 25 publica-
tions showed consistently improved BP control and reduced
left ventricular hypertrophy. However, the effects of daily he-
modialysis on quality of life, anemia, phosphorus control and
nutritional status were inconsistent. In 2008, Kjellstrand and
colleagues reported their long-term experience with 415 daily
hemodialysis patients (12), 265 treated at home and 150 treated
in-center. Patients were on daily dialysis for 2.4 ⫾ 2.6 yr, for a
total of 1006 patient-years. Forty-two percent of patients were
alive after 10 yr of daily hemodialysis and the death rate was 84
deaths of 1000 patient-years. When this survival rate was com-
pared with survival as reported in the USRDS 2005 Annual
Data report, and patients were matched for age, diagnosis and
place of dialysis, the relative rate of mortality of daily hemodi-
alysis patients was 0.35 to 0.83 of that of the matched USRDS
cohort. The standardized mortality ratio was 0.34, a highly
significant reduction in mortality. Life expectancy for the daily
dialysis patients was 9 to 15 yr longer than those of the matched
USRDS hemodialysis cohort, and was similar to deceased do-
nor kidney transplant recipients.
Nocturnal Home Hemodialysis
Nocturnal home hemodialysis (NHHD), performed four to
six times a week, offers the most marked enhancement of small
and large molecule clearance. It also allows for more gradual
ultrafiltration, enabling maintenance of “dry weight” with low
hourly ultrafiltration, favoring better survival (7). Walsh et al.
reviewed the published observational studies of NHHD (13).
Four patient cohorts from London and Toronto, Ontario,
Lynchburg Virginia and Rochester Minnesota, were examined.
Study sample sizes ranged from 5 – 63 NHHD patients fol-
lowed for 6 wk to 3.4 yr. Improved BP control, anemia and
health-related quality of life were consistent findings. There
also is evidence that NHHD upregulates genes responsible for
hematopoetic progenitor cells, increasing growth and produc-
tion of red blood cells (14). Sixteen patients treated with NHHD
showed increased hemoglobin from 11.3 ⫾ 0.3 to 12.5 ⫾ 0.4
Gm/dl with no change in erythropoetin or iron dose. This
group of investigators from Toronto has also shown evidence
from observational studies that NHHD reduces cardiovascular
related hospitalizations (15), improves the baroreflex effective-
Clin J Am Soc Nephrol 4: S121–S124, 2009
ness index and baroreflex sensitivity (16), improves sleep apnea
by increasing pharyngeal size (17) and improves cognition (18).
In 2007, Culleton and colleagues (19) published results of a
randomized controlled trial (RCT) comparing NHHD per-
formed five to six nights per week for a minimum of 6 h per
night to conventional thrice weekly hemodialysis. Left ventric-
ular mass decreased significantly in the NHHD group, while it
remained unchanged in the conventional dialysis patients. In
addition, BP fell with the use of fewer antihypertensives, and
phosphorus levels and parathyroid hormone levels fell in the
NHHD group. While the primary quality of life outcome was
not different than control, NHHD was associated with im-
provements in selected kidney-specific quality-of-life domains
(20). Although this study was not powered to examine survival
or hospitalization rates, this first published RCT of NHHD did
show improved cardiac and quality- of-life measures, which
have been shown to correlate with survival in dialysis patients
(21-23). This is an exciting finding, in light of previous RCTs
examining higher dose dialysis for end-stage renal disease
(HEMO (3) and ADEMEX (24) trials), and for acute kidney
injury (25) that failed to show a beneficial effect. If NHHD
really does offer improved outcomes, how likely is it that
patients will choose this dialysis modality? Cafazzo et al. re-
ported several patient-perceived barriers to NHHD (26). Fifty-
six nocturnal hemodialysis patients and 153 conventional he-
modialysis patients completed surveys concerning their
perceptions of their disease condition and overall health, ben-
efit, barriers and self-efficacy of NHHD and factors affecting
decision making. NHHD patients were healthier and had better
physical quality-of-life scores. The barriers to NHHD identified
were fear of self-cannulation, lack of confidence in conducting
NHHD and fear of a catastrophic event. The burden this ther-
apy placed on family members was also a perceived barrier.
The Frequent Hemodialysis Network (FHN)
Given the promising results of many observational studies
and a single RCT of more frequent hemodialysis, the National
Institute of Digestive Diseases and the Kidney and the Center
for Medicare and Medicaid Services have funded the FHN
trials. These two parallel RCTs, one examining short in-center
daily dialysis versus conventional thrice weekly dialysis, and
the other studying NHHD versus thrice weekly conventional
HD at home, are currently underway (27,28). We have recruited
and randomized 245 subjects in the daily in-center trial, and 87
subjects in the NHHD trial. Subjects will be studied in an
intention-to-treat analysis that compares outcomes after 1 yr.
These studies are not sufficiently powered to examine mortality
or hospitalization rates, so surrogate outcomes will be exam-
ined that we believe will correlate with mortality and with
quality of life, two outcomes of importance to dialysis patients.
Co-primary outcomes are: 1) a composite of 1-yr mortality and
change in left ventricular mass as measured by cardiac cine-
MRI, and 2) a composite of 1-yr mortality and change in RAND
Physical Health Component Score from the SF-36 quality-of-life
assessment tool. Secondary outcomes include assessments of
depression, cognitive function, nutrition and inflammation,
mineral metabolism, survival, hospitalization, hypertension
Clin J Am Soc Nephrol 4: S121–S124, 2009
and anemia. The study period will end in the first part of 2010,
and we expect to report results in 2010 and 2011.
Cost-Effectiveness of Frequent Hemodialysis
Given the high cost of treating dialysis patients, an important
question is what effect more intensive therapies will have on
the overall cost. Will more frequent treatments bring down the
cost of individual dialysis sessions? If more intensive dialysis
results in improved survival and reduced hospitalizations,
what effect will these have on costs? Lee and colleagues exam-
ined these questions for in-center daily hemodialysis using a
Monte Carlo simulation model (29). Inputs into the model
included various frequencies and duration of hemodialysis
(three to six times per week, 2 to 4.5 h per session), several
outcomes (costs, life expectancy and quality-adjusted life years)
and assumptions for the potential effects of frequent dialysis on
outcomes (for example, one input was a 32% reduction in
mortality with six times per wk treatments). They found that
the incremental cost-effectiveness ratio will be at least $75,000
per life year gained, and that none of the strategies using
six-times-per-week hemodialysis achieved a cost-effectiveness
ratio of less than $125,000 per life-year gained. Since we live in
a world where payers often seek “cost-neutral” treatment so-
lutions, they asked the question, under what circumstances
might costs “break even” – i.e., what improvements in out-
comes would be needed to result in no net increase in cost?
Their model suggested that costs could break even if the per-
session dialysis costs were reduced between 32% and 43%.
Might reduced hospitalizations result in costs breaking even?
Their model showed that for four-times-a week dialysis, hos-
pitalization rates would have to be reduced to 46% of current
rates for cost to break even. For five-times-a-week treatments,
hospitalizations would need to be completely eliminated to
break even, and six times-a-week treatments will never break
even. They conclude that more frequent in-center hemodialysis
strategies would likely increase ESRD program costs consider-
ably. They suggest that transition to home-based therapies will
be required to derive any benefit that might be present without
incurring excessive costs.
The International Quotidian Dialysis Registry
Well-designed studies examining mortality and hospitaliza-
tion for patients with heart disease are plentiful, but are re-
markably few in nephrology (30). This may in part be the result
of the many patients with heart disease, compared with the
relatively few with advanced kidney disease. ESRD patients
may be particularly reluctant to enroll in RCT because of their
multisystem disease and the toll that dialysis takes on their
lives (31). For whatever reason this difference exists, the low
numbers of patients willing to enter RCTs make assessments of
hard endpoints such as mortality and hospitalization rates dif-
ficult to assess: previous studies are underpowered to examine
these outcomes. Perhaps the best chance to assess them will
come with the International Quotidian Dialysis Registry (32).
This registry, established in 2002, has enrolled more than 2700
patients, all on alternate hemodialysis schedules. Patients are
accepted into the registry if they receive more than 5 h per
Intensive Hemodialysis S123
thrice-weekly treatment session or ⱖ5 treatment sessions per
week. Treatments may be daytime or nightly, in-center or at
home. The order of magnitude higher number of enrolled sub-
jects studied prospectively should allow analysis of mortality
and other clinical endpoints for these alternate dialysis regi-
mens.
Conclusions
• More intensive dialysis is needed to improve patient out-
comes.
• NHHD reduces left ventricular hypertrophy.
• Observational trials suggest better anemia care, phosphorus
control, fluid and BP management, baroreflex sensitivity,
cognition and less sleep apnea with intensive hemodialysis.
• Retrospective analysis shows improved survival with inten-
sive dialysis.
• Cohort studies show reduced cardiovascular-related hospi-
talizations with NHHD.
• Frequent in-center hemodialysis (four to six treatments/wk)
is more costly – unless per-treatment costs fall.
• Frequent home hemodialysis (four to six times a week) and
NHHD are promising, but are currently utilized by few
patients.
• INHD is the fastest growing type of more intensive hemo-
dialysis, with more efficient use of facility space, improving
financial viability.
• The FHN, two RCT of NHHD and daily in-center hemodi-
alysis are in progress.
• The International Quotidian Dialysis registry may give us
meaningful information on the effect of intensive hemodial-
ysis on mortality and hospitalization.
Disclosures
None.
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