Editorials
Progressive Hemodialysis: Is It The Future?
Carmelo Libetta,*† Peni Nissani,† and Antonio Dal Canton*†
*Unit of Nephrology, Dialysis, Transplantation, Fondazione I.R.C.C.S. Policlinico San Matteo, Pavia, Italy, and
†University of Pavia, Pavia, Italy
ABSTRACT
Progressive hemodialysis is based on the simple idea of
adjusting its dose according to residual renal function
(RRF). The progressive, infrequent paradigm is slowly
gaining a foothold among nephrologists, despite a lot of
skepticism in the scientific world. Given the importance of
RRF preservation in conservative therapy, it seems a con-
tradiction to ignore the contribution of RRF when
patients initiate hemodialysis (HD), especially when it is
routinely considered with peritoneal dialysis. While a
three-times-weekly HD regimen is broadly considered the
The three-times-weekly hemodialysis (HD) regi-
men, broadly considered the standard starting regi-
men for new patients, was empirically established
by the father of modern dialysis, Belding Scribner
(1). As then it has been assumed, until recently,
almost as a dogma in the dialysis community (2,3),
despite no real evidence based on randomized
clinical trials. However, this regimen is now consid-
ered by some, at least initially, to some extent as
gratuitous. An increasingly considered approach is
a progressive (or incremental) dialysis regimen
which is tailored to each individual patient’s condi-
tion and needs. It starts from a lower dose which
increases as residual renal function (RRF) and
urinary output (UO) decline.
Infrequent dialysis (less than three-times-weekly
HD) is an emerging new paradigm for HD initia-
tion (4). Historically, its use has been sporadic but
has recently been adopted more widely in different
countries, in some as a routine practice.
While medical considerations are of primary
importance, it is obvious that a progressive
approach, starting with a twice-weekly, or even
once-weekly regimen, will cut the total cost of dialy-
sis, freeing resources that could be directed to other
health and social service needs. Additionally, ESRD
Address correspondence to: Carmelo Libetta, MD, PhD,
Fondazione IRCCS Policlinico S. Matteo, Piazzale Golgi 2,
Pavia 27100, Italy, e-mail: carmelo.libetta@unipv.it.
Seminars in Dialysis—Vol 29, No 3 (May–June) 2016
pp. 179–183
DOI: 10.1111/sdi.12455
© 2015 Wiley Periodicals, Inc.
179
standard starting regimen for new patients, twice-weekly
HD has been used in selected patients and is currently a
common practice in South-East Asia. Small studies indi-
cate that a once-weekly HD regimen may be a viable
starting option as well. Progressive hemodialysis still
requires validation, yet it is promising. We share the belief
that a randomized clinical trial to investigate progressive
hemodialysis is much needed, but we also strongly recom-
mend including a once-weekly HD starting dose as part
of any such investigation.
and dialysis are becoming increasingly a geriatric
issue rather than just a nephrology issue focusing
more attention on improving a patient’s indepen-
dence and quality of life. Progressive HD may
favorably impact these areas.
Importance of Residual Renal Function and
Urinary Output
Residual renal function is simply defined as the
GFR that a patient’s failing native kidneys are still
able to supply. RRF is roughly approximated by
measuring UO. While RRF and UO do not mea-
sure the same physiological quantity—the former is
a clearance while the latter is just a fluid volume—
they are closely related.
The importance of maintaining the RRF in peri-
toneal dialysis (PD) was well established by the
CANUSA study (5,6). This has lately been extended
to HD as well, including a positive association of
RRF with decreased mortality (7–13). Current dial-
ysis regimens appear to only partially replace native
kidney function in its purification role; whether dial-
ysis’ deficit is removal of middle-weight (or protein
bound or slow moving intracellular) molecules with
uremic toxicity, its intermittent volume excursions
or other factors is unknown (14).
Although UO has acquired an increasing impor-
tance in HD patients, there is an important dichot-
omy between UO and cardiovascular risk in such
patients. This dichotomy is best illustrated by the
results of the Frequent Hemodialysis Network
180
(FHN) trial. In it, frequent HD (six-times-weekly)
decreased cardiovascular risk compared to standard
three-times-weekly HD (15) although standard HD
better maintained a patient’s baseline UO compared
to the frequent HD (16). Other studies appear to
confirm that on one hand, less frequent HD tends
to preserve UO and RRF with all their benefits
while on the other hand, more frequent HD lowers
cardiovascular risk. It is a Janus-faced dilemma
(17).
The decline in UO seen in patients on frequent
HD may be due to a more aggressive (and success-
ful) attempt to reach a patient’s dry weight and
the adverse hemodynamic consequences of this on
RRF. Given the association of RRF with lower
mortality, the results of the FHN trial group seem
to suggest that for many or most patients the
cardiovascular benefits of frequent HD overshadow
the ill effects of lost RRF. However, for selected
HD patients with a low cardiovascular risk, the
benefits of maintaining UO (and RRF) might be
an appropriate therapeutic target even considering
any slight detriment with regard to cardiovascular
risk.
Twice-weekly HD
In a recent article Kalantar-Zadeh et al. suggested
criteria by which patients could be selected for a
less frequent, twice-weekly HD scheme (Table 1)
(18). Twice-weekly HD has been used in the past,
almost as an “off label” practice, in the United
States and other western countries. The KDOQI
guidelines actually support this approach for
patients with residual renal urea clearance >2 ml/
minute and minimum standardized Kt/V target >2
per week (19).
Libetta et al.
In 1999, a retrospective study analyzed this
practice in the United States (20). From the data
available on 15,343 patients it was shown that
twice-weekly HD was mostly applied to older Cau-
casian women with higher serum albumin levels
(sign of better nutritional state and minimal inflam-
mation), lower serum creatinine levels (sufficient
RRF and UO), lower BMI (possibly lower preva-
lence of metabolic syndrome issues such as diabetes
and hypertension) and recent initiation of dialysis.
A few prospective studies have also been carried
out in the past decade. In 2012 a Spanish study
indicated significant advantages in the twice-weekly
group: better survival, slower RRF and UO decline,
lower b2-microglobulin concentration (more effi-
cient blood purification from RRF) and lower EPO
requirements EPO (21,22).
A comparison in Taiwan between twice and
three-times-weekly HD showed instead no differ-
ences in survival or hospitalization, although the
twice-weekly group had advantages with respect to
b2-microglobulin concentration, RRF decline and
intradialytic hypotensive episodes (23). Two Chinese
studies confirm these latter results (24,25).
In the Far East the twice-weekly HD regimen
appears to be a more common practice with other
reports in the literature (26,27). It is not then a
surprise that the recent scientific arguments sup-
porting progressive HD originate from this region.
Two negative experiences with twice-weekly HD
from Lithuania and Sudan deserve mention
(28,29). However, these experiences are of limited
value because there are no data about RRF or
UO and, more importantly, the choice between
twice and three-times-weekly HD was probably
made based on the resource limitations rather than
clinical conditions.

TABLE 1. Criteria for twice-weekly HD (from Kalantar-Zadeh
et al. (18), with modifications)
1 Good RRF with urine output >0.5 l/day
2 Limited fluid retention between 2 consecutive HD treat-
ments with fluid gain <2.5 kg (or <5% of ideal dry
weight) without HD for 3 or 4 days
3 Limited or readily manageable cardiovascular or pul-
monary symptoms without clinically significant fluid over-
load (lack of systolic dysfunction with ejection fraction
>40% and no major coronary intervention over the previ-
ous 3 months)
4 Suitable body size relative to RRF; patients with larger
body size may be suitable if not hypercatabolic
5 Hyperkalemia (K > 5.5 mEq/l) is infrequent or readily
manageable
6 Hyperphosphatemia (P > 5.5 mg/dl) is infrequent or
readily manageable
7 Good nutritional status without florid hypercatabolic
state
8 Lack of profound anemia (Hb >8 g/dl) and appropriate
responsiveness to anemia therapy
9 Infrequent hospitalization and easily manageable comor-
bid conditions
10 Satisfactory health-related quality of life
Once-weekly HD
The discussion of progressive HD should also
include once-weekly treatment. This treatment, com-
bined with a hypoproteic diet, was developed in the
1980s and 1990s (30–33), mostly from Italian
research groups. This idea, which has survived
among some nephrologists in Italy but was soon
forgotten elsewhere, has been recently reevaluated
in a multicenter study (34). In this study, 68 inci-
dent patients were enrolled and given free choice
between three-times-weekly and once-weekly HD
the latter with a hypoproteic diet. The once-weekly
group showed a slower decline in RRF, lower
serum b2-microglobulin concentrations as well as a
slight survival advantage and a reduced hospitaliza-
tion rate after 24 months. Furthermore, the annual
cost per patient was considerably lower .
Libetta et al. also conducted a preliminary, 16
patient study of a once-weekly starting regimen
(35). Patient quality of life significantly improved
compared to that seen in patients on the standard
three-times-weekly regimen. Once-weekly treatment
 PROGRESSIVE HEMODIALYSIS
also significantly protected RRF and maintained
lower levels of b2-microglobulin.
A once-weekly starting regimen in a progressive
HD context was also described by Keshaviah et al.
in 1999. They developed a urea kinetic model to
show how the HD dose can be titrated to compen-
sate for declining renal function while maintaining a
constant total combined dose of renal and dialytic
clearance (36). Based on their theoretical model they
recommend to directly start with twice-weekly HD
to minimize wide swings in the serum concentra-
tions of small-weight solutes. At the time, the many
benefits of RRF and UO were not taken into
consideration (37).
The progressive approach to HD
Progressive HD should be considered a bridge
between conservative therapy and full renal replace-
ment therapy (RRT). Conceptually, its purpose is
to lengthen the time span in which patients can
continue to rely (partially) on their native kidneys
and need not initiate complete replacement of their
kidneys with full-dose dialysis.
Its key is to maintain RRF and UO as long as
possible to keep body volume and, consequently,
cardiovascular risk under control. Of course this
can be done only in selected patients with a low
cardiovascular risk, as already suggested by
Kalantar-Zadeh et al. (18).
The method for applying progressive dialysis has
not been standardized; however, the general
approach can be summarized with a diagram
(Fig. 1). Three steps in the dialytic therapy are
described: step 1—once-weekly HD associated with
hypoproteic diet and conservative therapy; step 2—
twice-weekly HD for patients experiencing a decline
in RRF and UO; step 3—three-times-weekly HD
for patients whose RRF and UO is not adequate
anymore and must be shifted to a full-dose dialytic
replacement therapy.
Objective criteria to step up, or even down,
within the ladder must still be agreed upon. It is
clear, although, that in order to proceed safely, it is
Fig. 1. Framework for a progressive approach to hemodialysis.
181
mandatory to monitor RRF regularly (preferably
monthly) in all patients on progressive HD.
Risks of Progressive Hemodialysis
Progressive HD is certainly not risk free. It
clearly requires close attention to a patient’s clinical
condition and chemistries in addition to RRF.
Urine collections are notoriously inaccurate. Deteri-
oration in a patient’s chemistries or volume status
may be unexpectedly abrupt and life threatening.
Uremia, a still somewhat mysterious condition, may
present in ways that are not being monitored closely
(eg pericarditis, neuropathy) and may be problem-
atic in their therapy. Even when patients are being
properly monitored, they may find once or twice-
weekly treatment to their liking and refuse more fre-
quent HD regardless of the clinical indication and a
nephrologist’s entreaties. Whether the benefits of
progressive HD outweigh these and other risks is
still to be determined.
Other Considerations Supporting the
Progressive Approach
Whether one starts HD with one, two or three
weekly treatments still leaves open the question of
when to start any dialysis at all. Bonomini et al.
(38,39) suggested starting as early as possible. Later,
other data indicated instead a better survival with a
late start (40–45). In 2010 the results of the Initia-
tion of Dialysis: Early And Late (IDEAL) study, a
randomized clinical trial designed to answer this
question, were published (46) and showed neither
an advantage nor a disadvantage in terms of mor-
tality in patients starting dialysis early. The debate
is still open (47,48); however, everybody agrees that
early referral is essential and improves outcomes
substantially (49–51). The mortality of HD patients
in the first few months of treatment is dramatically
high. Kalantar-Zadeh et al. have theorized that one
of the reasons to explain this early mortality in HD
patients is that the standard three-times-weekly
starting regimen suddenly distorts the patient’s
homeostasis (18). If this theory is correct, the pro-
gressive approach might significantly reduce early
mortality.
Measurement of RRF and Dialytic Adequacy
Residual renal function is assessed by directly
measuring residual renal urea clearance (KRU)
from serum and urine concentrations. A method to
combine both the native kidney contribution, KRU,
and the dialyzer contribution, measured as Kt/V
(52), is needed to assess patients. The two contribu-
tions are incomparable not simply because the phys-
ical units differ but also because the former is
continuous while the latter is intermittent. In order
to compare and combine them, one must be
182
TABLE 2. Mathematical formulae to combine residual renal function and dialytic adequacy
Casino and Lopez (53):
19 week (step 1): ð1Þ EKRc ¼ 0:7 þ 3  Kt=V
29 week (step 2): ð2Þ EKRc ¼ 1 þ 6:2  Kt=V
39 week (step 3): ð3Þ EKRc ¼ 1 þ 10  Kt=V
Kt=V
10; 080  1e
Leypoldt et al. (55): ð4Þ stdKt=V ¼ 1eKt=V 10;080t
Kt=V þ Nt  1
 Kt=V

10;0801e t
Daugirdas et al. (56): ð5Þ 1eeKt=V 10;080
þ Nt 1
stdKt=V ¼
eKt=V
1  0:74
N  V
UFw
In these equations: “EKRc” is the equivalent renal urea clearance (measured in ml/minute), “stdKt/V” is the standardized Kt/V,
“spKt/V” is the single-pool Kt/V, “eKt/V” is the equilibrated Kt/V, “Kt/V” is either the single-pool or the equilibrated Kt/V, t is the
duration of dialysis (measured in minutes), N is the frequency of dialysis (N 9 week), “UFw” is the weekly ultra-filtration (measured in
mL) which corresponds to the weekly body volume gain, and “KRU” is the residual renal urea clearance (measured in ml/minute).
converted to the other (even while acknowledging
other impediments to such a simplistic approach).
Casino and Lopez were the first to convert the
dialyzer contribution, represented by the Kt/V, to
an equivalent renal urea clearance (EKRc) (53).
They developed different equations for each HD
regimen (eqs 1–3 in Table 2). Adding EKRc to
KRU gives a good estimate of the combination of
the native and the artificial kidney components
needed to evaluate therapy. Thresholds will need to
be set to help the physician decide when to change
the frequency of HD.
The other way around, namely to convert, or bet-
ter said, include KRU in the Kt/V calculation, is also
possible thanks to the concept of weekly standard-
ized Kt/V, introduced almost two decades ago (54).
This concept was refined by Leypoldt et al. with an
equation to calculate standardized Kt/V from single-
pool or equilibrated Kt/V, duration of dialysis and
frequency of dialysis (eq. 4 in Table 2) (55).
As the Kt/V target should be 1.2 according to the
guidelines, analogously the weekly standardized Kt/
V target should be 2.0 or slightly higher. However,
these therapeutic targets for dialytic adequacy will
deliver what might be considered overtreatment in
those patients with significant RRF. Unfortunately,
Leypoldt’s equation does not include KRU, but
new models overcome this limitation. Daugirdas
et al. developed an equation that, in addition to sin-
gle-pool or equilibrated Kt/V, takes into account
duration and frequency of dialysis, weekly body
volume gain and KRU (eq. 5 in Table 2) (56).
Equations such as Daugirdas’ can be adopted in
patients on progressive HD but with reservations
because they were based on data collected from
incomparable patients. For instance, Daugirdas’
equation was obtained from the FHN trials where
only three-times-weekly and six-times-weekly HD
regimens had been prescribed. More reliable equa-
tions for standardized Kt/V must be eventually
developed using data collected from patients on
progressive HD.
Libetta et al.
 
0:974 10; 080
þ KRU  þ 0:4 
spKt=V þ 1:62 V
Conclusions
Progressive HD, based on an adjustment of dialy-
sis dose according to RRF and UO (Fig. 1), is slowly
gaining adherents among nephrologists (4,18,57–59)
although much skepticism still exists (60).
While the value and safety of progressive dialysis
still needs to be proven, it is promising. The
nephrology community has been engaged in an hon-
est and fruitful discussion on the duration of HD; it
is time to more extensively discuss its frequency on
the low end as well as the high.
In our clinical experience, starting with a once-
weekly HD dose is, in selected patients, a suitable
and convenient option. We share the feeling that a
randomized clinical trial to investigate progressive
HD is much needed, and recommend including the
once-weekly HD starting dose as part of any future
investigation.
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