Editorial
When to Initiate Dialysis in Children and
Adolescents: Is Waiting Worthwhile?
Edward Nehus and Mark M. Mitsnefes
D espite improvements in the care of pediatric patients
with end-stage kidney disease, children receiving
dialysis continue to have unacceptably high mortality, with
an average lifespan that is 30 to 40 years shorter compared
Related Article, p. 797
with individuals matched for age and ethnicity.1,2 Current
strategies to improve patient survival include preemptive
transplantation and expedited transition from dialysis to
transplantation. But what about the children who must
have long-term dialysis? What is the best approach to
improve long-term outcomes in this population, including
the timing of dialysis initiation? If receiving maintenance
dialysis even for a few months is associated with increased
mortality,2 could delaying dialysis initiation for a few
months have a survival benefit for these children?
In adults, the Initiating Dialysis Early and Late (IDEAL)
Study addressed this question in a landmark randomized
controlled trial that investigated patient outcomes at
early (estimated glomerular filtration rate [eGFR] of 10-
15 mL/min/1.73 m2) versus late (eGFR of 5-7 mL/min/
1.73 m2) dialysis initiation.3 The primary findings showed
no difference in all-cause mortality, hospitalizations, and
cardiovascular events between early and late dialysis start,
and this had a profound effect on clinical practice in the
United States and around the world. Accordingly, the
updated 2015 KDOQI (Kidney Disease Outcomes Quality
Initiative) clinical practice guideline for hemodialysis ad-
equacy specifically emphasizes that symptoms and signs
associated with chronic kidney disease (CKD) complica-
tions, rather than a specific eGFR, should guide a decision
to initiate dialysis.4 As a result, there has been a shift in
timing of initiation maintence dialysis in adults. The 2018
US Renal Data System (USRDS) Annual Data Report indicated
that the mean eGFR at initiation of dialysis in 2016
was 9.7 mL/min/1.73 m2, down from a peak of
10.4 mL/min/1.73 m2 in 2010.1
In children, the indications to initiate maintenance
dialysis are in many ways similar to those in adults and
consist of a combination of clinical (eg, uncontrolled hy-
pertension, edema, and inability to provide adequate
nutrition) and biochemical (eg, hyperkalemia, hyper-
phosphatemia, and acidosis) characteristics.5-7 But what
about specific recommendations regarding eGFR and
dialysis initiation? The early guidelines, based on experts’
opinions for peritoneal dialysis (2001)5 and hemodialysis
(2006),6 recommended starting dialysis when eGFR is 10
to 15 mL/min/1.73 m2. Data from a European registry
collected between 2002 and 2007 demonstrated that the
762
median eGFR at dialysis initiation was 10.0 mL/min/
1.73 m2 for peritoneal dialysis and 10.3 mL/min/1.73 m2
for hemodialysis.8 The 2014 review on the optimal care of
children receiving dialysis argued that “dialysis should be
considered when the patient’s eGFR decreases to 10-15
(United States: 9-14) mL/min/1.73m2, and recommended
when eGFR is below the lower end of this range.”7(p129)
Remarkably, although the IDEAL trial and many
observational studies have investigated the effect of eGFR
on mortality at the time of dialysis initiation in adults,9
there have been no studies examining this important
issue in children. In this issue of AJKD, Okuda et al10 filled
this gap. Using USRDS data collected from almost 10,000
children and adolescents who were aged 1 to 17 years old
between 1995 and 2016, they conducted a retrospective
cohort study to examine the association between eGFR at
time of initiation of maintenance dialysis and risk for
mortality.
The main findings of this pediatric study are consistent
with the results of many adult studies: in adjusted models,
compared to a reference eGFR of 7 to <9 mL/min/
1.73 m2, hazard ratios for mortality were 0.57 (95%
confidence interval [CI], 0.43-0.74) and 1.31 (95% CI,
1.05-1.65) in those with eGFRs < 5 and ≥12 mL/min/
1.73 m2, respectively. These associations were significant
in children and adolescents 6 years and older; no differ-
ence in mortality risk according to eGFR was seen in those
younger than 6 years. Although during the last few years
there has been a trend to initiate dialysis at lower eGFRs in
adults, the opposite trend was seen in the current study:
median eGFRs were 8.8 mL/min/1.73 m2 in 2010 and
10.0 mL/min/1.73 m2 in 2016.
At first glance, a straightforward interpretation of these
results suggests that, as in adults, clinical practice of dial-
ysis initiation at relatively high eGFRs needs to be changed
to lower eGFRs. However, the authors, to their credit,
did not make these specific recommendations. They
acknowledge many limitations of the observational study,
including the potential for residual confounding and sur-
vivor bias. These limitations deserve particular attention
because observational studies in adults that have used more
robust statistical methods to address residual confounding
and survivor bias (such as inverse probability weighting
and instrumental variable analyses) have failed to show an
association of higher eGFR at dialysis initiation with pa-
tient mortality.11,12
The survival benefit and mortality risk in this study were
most apparent in groups at the extreme ends of the eGFR
distribution, that is, patients with eGFRs < 5 or >12 mL/
min/1.73 m2. In contrast, no significant association of
AJKD Vol 73 | Iss 6 | June 2019
Editorial
eGFR with patient mortality was evident in the interme-
diate eGFR levels of 5 to 12 mL/min/1.73 m2, the range at
which dialysis is most commonly initiated (63% of inci-
dent patients). The 19% of patients who were able to
initiate dialysis with an eGFR < 5 mL/min/1.73 m2 may
have been a healthier cohort because most patients, for
various reasons, are unable to postpone dialysis initiation
to this level of eGFR. Conversely, children who started
dialysis at a relatively high eGFR may have had other CKD-
related comorbid conditions that necessitated earlier
initiation of dialysis and conferred additional morality risk.
The trajectory of eGFR decline represents another po-
tential source of confounding. In clinical practice, the
decision to start dialysis, particularly peritoneal dialysis in
children, is often made assuming a continued decline in
eGFR based on recent trends. Recent data indicate that
decline in residual kidney function during dialysis is
strongly predictive of patient mortality.13 It is possible that
patients who started dialysis at lower eGFRs had a more
indolent progression of disease and maintained residual
kidney function after dialysis initiation, whereas a more
precipitous decline in residual kidney function occurred in
those who initiated dialysis earlier. Therefore, while the
results of the current study contribute to a growing body
of adult literature that indicate early initiation of dialysis is
not associated with improved outcomes, it would be
premature to conclude that there is a definitive benefit to
deliberate postponement of dialysis initiation.
There are also some important differences between
children and adults with end-stage kidney disease that
need to be considered when addressing the issues of eGFR
decline and dialysis initiation, in particular regarding
definitive recommendations of dialysis initiation. The
progression of CKD in children, in contrast to adults, can
have a significant impact on physical and neurocognitive
development. At the initiation of dialysis, approximately
one-quarter to one-third of children have growth delay.14
Developmental delay is more difficult to assess, but appears
to be present in at least 25% of infants and young children
with severe CKD.15 A major goal of CKD care in the pe-
diatric population is therefore to preserve, as much as
possible, normal physical and neurologic maturation. In
this setting, early initiation of dialysis may assist in the
management of comorbid conditions that are associated
with delays in growth and neurocognitive development,
such as hypertension, acidosis, malnutrition, and ane-
mia.15-18 In the analysis by Okuda et al,10 patient mortality
was the only outcome evaluated. In the absence of any
definitive research that investigates the timing of dialysis
initiation in children and its effect on childhood devel-
opment, initiation of dialysis at higher eGFRs seems
reasonable if growth and developmental delays are present.
Despite the limitations of the study, the results provide a
timely addition to the pediatric literature that calls into
question the practice of dialysis initiation at higher GFRs.
Delayed initiation of dialysis, if this can be safely achieved,
may be beneficial by postponing exposure to the
AJKD Vol 73 | Iss 6 | June 2019
psychological and physical burdens that are associated with
maintenance dialysis.19 An especially important consider-
ation in this regard is the progression of cardiovascular
disease (CVD) in children receiving maintenance dialysis.
The results of Okuda et al confirmed CVD as the most
common cause of mortality in children receiving dialysis,
accounting for approximately one-third of all deaths.
While cardiovascular risk factors and subclinical cardiac
and vascular abnormalities are present in children before
dialysis, CVD quickly accelerates after dialysis initiation.20
Exposure to dialysis provides a perfect storm of risk factors
leading to maladaptive cardiomyopathy, accelerated
athero- and arteriosclerosis, and vascular calcification.20,21
Initiation of dialysis at eGFRs just a few points lower than
currently recommended would likely delay it by several
months, as was seen in the IDEAL trial.3 In that study,
although the mean difference in eGFRs at dialysis initiation
was only 2.2 mL/min/1.73 m2, dialysis was postponed by
5.6 months in the late-start group. One can only speculate
whether delayed dialysis initiation would have any effect
on the progression of CVD in children.
Based on the results of this study, the pediatric
nephrology community may need to reevaluate the current
recommendation of dialysis initiation when eGFR de-
creases to just <10 mL/min/1.73 m2 and adopt a practice
that is more closely aligned with the most recent KDIGO
(Kidney Disease: Improving Global Outcomes) recom-
mendations. However, particular attention must be given
to the growth and development of children approaching
end-stage kidney disease, and dialysis should not be
withheld in the presence of significant delays in these
parameters despite a relatively high eGFR. Most impor-
tantly, the timing of dialysis initiation should balance the
risks and benefits of the procedure while incorporating a
patient-centered approach that encourages caregiver
participation in the decision-making process. In this re-
gard, Okuda et al are to be commended for this important
contribution, which can assist both the provider and
caregiver in achieving such a goal.
Article Information
Authors’ Full Names and Academic Degrees: Edward Nehus, MD,
MS, and Mark M. Mitsnefes, MD, MS.
Authors’ Affiliation: Division of Nephrology and Hypertension,
Cincinnati Children’s Hospital Medical Center, University of
Cincinnati, Cincinnati, OH.
Address for Correspondence: Mark M. Mitsnefes, MD, MS, Division
of Nephrology and Hypertension, MLC: 7022, 3333 Burnet Ave,
Cincinnati, OH 45229-3039. E-mail: mark.mitsnefes@cchmc.org
Support: None.
Financial Disclosure: The authors declare that they have no
relevant financial interests.
Peer Review: Received January 2, 2019, in response to an invitation
from the journal. Direct editorial input from an Associate Editor and a
Deputy Editor. Accepted in revised form February 9, 2019.
Publication Information: © 2019 by the National Kidney Founda-
tion, Inc. Published online April 5, 2019 with doi 10.1053/
j.ajkd.2019.02.008
763

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