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11  Preservation of Residual Renal Function in Children Reaching End-Stage Renal Disease

Rapid somatic growth and gain in body weight
are associated with accelerated deterioration of
renal function [42]. Patient age, reflecting body
growth, is a general risk factor for progression in
children [41, 42, 80]; specifically, adolescents
seem to progress more rapidly than prepubertal
patients. Accelerated disease progression during
puberty has been observed in patients with CKD
due to diabetes mellitus, posterior urethral valve,
reflux nephropathy, and renal hypoplasia [81].
The physiological pubertal rise in blood pressure,
an increased metabolic load due to statural
growth which cannot be compensated by proportionate renal growth, and vascular or tissue-­
specific effects of sex steroids are possible
mechanisms underlying these associations. On
the other hand, administration of recombinant
human growth hormone (rhGH), which induces
body growth, was not associated with accelerated
loss of renal function in children [82].
Interestingly, in adult patients on long-term
dialysis, obesity is associated with an accelerated
decline of RRF [50, 73, 83].
The role of genetic factors in determining the
rate of renal failure progression is not yet fully
understood. Whereas no gender difference has
been noted in CKD and ESRD cohorts encompassing the pediatric age range [41, 66], GFR
appears to decline more rapidly in adult and adolescent males [34, 58], compatible with an
adverse impact of androgens (or a protective
effect of female sex steroids) on the conservation

of RRF in CKD.  However, in children on PD,
RRF was not affected by gender [45, 51].
African-American ethnicity is a significant
risk factor of progression in pediatric CKD
patients [41]. Non-white race also predicts rapid
loss of RRF in adults on dialysis [69].
Increasing evidence suggests that the individual variability of CKD progression may in part be
related to common genetic and epigenetic variation. The DD genotype, a common variant of the
ACE gene, was found overrepresented in pediatric ESRD as compared to the general population
[84]. This was confirmed in children with hypodysplasia, obstructive uropathy, and reflux
nephropathy, but not in those with other congenital or hereditary diseases or acquired glomerular

161

disorders [85]. Other studies suggested an association of the DD genotype with declining renal
function also in pediatric glomerular diseases
with normal renal function [86, 87]. Furthermore,
single nucleotide polymorphisms (SNPs) in the
transforming growth factor-beta1, KLK1, and
vascular endothelial growth factor genes were
reported to modify the risk of renal deterioration
in reflux nephropathy [80, 88]. SNPs in the
D-loop of mitochondrial DNA allele 146 were
identified as an independent predictor of kidney
survival time [89]. Glutathione-S-transferase-μ1
(GSTM1) null and apolipoprotein L-1 (APOL1)
high-risk alleles were also reported to affect CKD
progression with hypertension [90, 91].
Moreover, several microRNAs (miR-30d, miR-­
140-­3p, miR-532-3p, miR-194, miR-190, miR-­

204, miR-206) were downregulated in renal
tissues from progressive CKD [92].
Recently, a genome-wide association study
(GWAS) identified several genetic variants associated with the decline of renal function in adults
with CKD. SNPs in LINC00923 was associated
with CKD progression and variants in genes,
NAT8B, CASP9, and MUC1, with estimated
GFR [93, 94]. The Pediatric Investigation for
Genetic Factors Linked with Renal Progression
(PediGFR) consortium identified 10 SNPs associated with estimated GFR across three large
pediatric CKD cohorts [95].

 pecific Risk Factors for Loss of RRF
S
in Patients on Dialysis
RRF decreases with time on dialysis [69], and the
loss over time is exponential rather than linear
[52]. In adult patients on hemodialysis and PD,
the decline of RRF was most prominent during
the first 3 months after the start of dialysis [37].
Repetitive intravascular volume depletion and
hypotensive events are considered important
causes of a rapid loss of RRF [73].
The choice of dialysis modality has a crucial
impact on RRF. There is ample evidence both in
adults and in children that RRF is preserved better with PD than with hemodialysis [51, 56, 69,
96, 97]. A more than two times faster decline of


I.-S. Ha and F. Schaefer

162
Fig. 11.3  Time to
oliguria (daily diuresis
<500 mL/m2) in children
with ESRD treated by
peritoneal vs.
hemodialysis. (Modified
from Ref. [98])

100
PD
HD

%

75

50

25

0
0

180

360

540

720

900

1080

1260

Days

RRF was observed in adult patients on HD compared to those on CAPD [69, 96]. In children, a
retrospective study revealed that daily urine volume less than 500 mL/m2 in 50% of patients was
reached significantly earlier (within 175  days)
after start of HD than after commencement of PD
(within 916  days) (Fig.  11.3) [98]. This difference is believed to be mainly due to the rapid
removal of large amounts of fluid by intermittent
extracorporeal procedures, leading to acute hypotensive episodes, generalized vasoconstriction,
tissue hypoperfusion, and lower preglomerular
arterial pressure. In addition, the contact of blood
with artificial bioincompatible membranes triggers activation of complement system and circulating leukocytes with subsequent release of
nephrotoxic inflammatory mediators, which may
cause a chronic state of inflammation and acceleration of fibrogenesis at the tissue level [56, 96].
In a study comparing automated PD and hemodiafiltration, automated PD was still associated
with a better preservation of RRF than hemodiafiltration despite the use of biocompatible membrane and high hemodynamic stability during the
procedure [99].
Though there are controversies [100–102],
majority of the studies failed to reveal difference
in RRF loss between automated PD and CAPD

[51, 103–107]. The tidal variant of APD was
reported to preserve RRF better than nontidal
modalities [108].
Peritonitis frequency was associated with RRF
decline in adult patients on PD [50, 52]. This
observation may be explained by hypotensive
episodes related to systemic infection and also to
the common use of nephrotoxic antibiotics such
as vancomycin and aminoglycosides. Whereas
empirical use of aminoglycosides (usually terminated within 2–3 days) in peritonitis has not been
found to affect RRF in adult patients [109, 110],
administration of aminoglycoside for at least
3 days was correlated with more rapid decline of
RRF [111].

 linical Management Options
C
to Slow CKD Progression
and Preserve RRF on Dialysis
Two management principles show promise to
slow down the rate of renal functional loss both
in the pre-dialysis stage and when dialysis-­
dependent renal failure has already occurred: to
avoid known and suspected risk factors for
­progression as much as possible and to apply
renoprotective therapies.


11  Preservation of Residual Renal Function in Children Reaching End-Stage Renal Disease

Avoidance of Risk Factors

163

RRF. If for some reason hemodialysis is chosen,
careful monitoring of the volume status and
avoidance of dehydration and hypotensive events,
as well as hypertension, volume overload, and
congestive heart failure, are crucial to minimize
the rate of RRF loss.
Finally, the administration of nephrotoxic
drugs such as aminoglycosides should be minimized, and any measures to reduce the rate of
peritonitis will impact beneficially on the conservation of RRF.

Half of the risk factors listed above are principally modifiable. Most of them are detrimental
per se to patient health irrespective of their impact
on CKD progression and should be avoided in
their own right, even though direct causality has
not been universally demonstrated by prospective
studies. For example, strict control of hypertension, reduction of proteinuria (especially residual
proteinuria during RAS blockade), correction of
anemia, metabolic acidosis, hypoalbuminemia,
hyperlipidemia, hypocalcemia, hyperphosphatemia, hyperuricemia, congestive heart failure,
extracellular volume overload, and obesity; prevention and adequate treatment of UTI; and
avoidance of nephrotoxic agents are generally
recommended in patients with CKD. In addition,
some knowledge of the individual profile of non-­
remediable risk factors is also important since
patients at high risk may benefit particularly from
early renoprotective intervention and minimization of remediable risk factors.

In patients in need of dialysis, PD is preferred
to hemodialysis under the aspect of preserving

Blood Pressure Control
Interventional studies aiming at lowering blood
pressure in patients with CKD have provided evidence for a causative role of high blood pressure
in CKD progression. The randomized controlled
ESCAPE trial showed that intensified blood pressure control, with a target 24-h mean arterial
pressure below the 50th percentile, confers a substantial long-term benefit on renal function in
childhood CKD (Fig. 11.4) [48]. The risk of losing 50% GFR or progressing to ESRD was

Conventional glomerulopathies

100

Patients reaching primary
end point (%)

90
80
70
60

P = 0.004

50

Intensified glomerulopathies

40

Conventional
hypoplasia-dysplasia

30

P = 0.037

20

Intensified
hypoplasia-dysplasia

10
0
0

1

2

3

4

5

Years of observation

Fig. 11.4  Effect of intensified blood pressure control on

renal survival in children with hypo/dysplastic and glomerular disorders receiving fixed-dose ACE inhibition.
Red lines denote patients randomized to intensified blood

pressure target (<50th 24  h MAP percentile) and blue
lines denote those with conventional target (50–95th 24 h
MAP percentile). (Modified from Ref. [48])


I.-S. Ha and F. Schaefer

164

reduced by 35% after 5  years in the children
managed by strict blood pressure control. The
nephroprotective effect was significant both in
children with glomerulopathies and in those with
renal hypodysplasia.

RAS Inhibition
ACE inhibitors and angiotensin type-2 receptor
blockers (ARB) have the potential to slow CKD
progression and reduce proteinuria in patients
with CKD [35]. In pediatric nephropathies, RAS
antagonists reliably lower blood pressure and
proteinuria [112], but uncontrolled studies in
children with congenital abnormalities of the kidney and the urinary tract have yielded conflicting
results as to a specific renoprotective effect of
these agents [49, 113]. As in pre-end-stage CKD,
there are controversial results on the effect of
RAS inhibition on RRF in patients on dialysis

[45, 69, 114, 115]. In a large pediatric incident
PD cohort, the use of RAS antagonists was associated with a 50% increase in the risk of oligoanuria during prospective observation [45]. In a
randomized controlled trial in adult PD patients,
a time-dependent effect of ACE inhibition was
observed; RRF declined faster and the risk of
developing anuria was higher during the first
9 months, whereas RRF declined at a slower pace
and anuria occurred less frequently beyond
12  months of treatment [116]. This biphasic
effect of ACE inhibition may be explained by
hemodynamic mechanisms reducing GFR early
during treatment followed by nephroprotective
antifibrogenic effects prevailing with long-term
administration.
An additional renoprotective effect of add-on
ARB was reported in children with CKD who
were already treated with ACE inhibitors [117].
In this study, a significant but tolerable elevation
of serum potassium was noted, and the benefit
was noted in hemolytic uremic syndrome and
reflux nephropathy but not in congenital nephrotic
syndrome. However, in view of observations in
adult patients indicating increased loss of renal
function, hypotension, and hyperkalemia with
dual blockade [118], close monitoring of these

side effects is necessary. In adults, an intensive
therapy combining ACE inhibitor, ARB, spironolactone, and statin was reported to slow the progression more effectively [119].

Diuretics

In adults on hemodialysis and PD, loop diuretics
help maintain urine output [120–122]. We
recently confirmed the beneficial effect of loop
diuretics on residual diuresis in a prospective registry study of 400 non-oliguric children who
commenced PD [45]. Among the 72 patients
receiving furosemide from the start of dialysis,
only 10% turned oligoanuric within 30 months as
compared to 35% of those who did not receive a
diuretic (Fig. 11.5). This effect was independent
of age, underlying disease, urine volume at PD
start, PD prescription, and co-administration of
RAS antagonists. However, this beneficial effect
of diuretics on water balance may not accompany
better residual renal solute clearance. Studies on
adult dialysis patients suggested that renal urea
and creatinine clearances were not affected by
diuretic administration [121, 123], with some
even reporting an adverse effect on solute clearance [54, 55].

Peritoneal Dialysis
In PD, use of more biocompatible PD fluids with
markedly reduced content of glucose degradation
products (GDP) contributes to preserving the
structural and functional integrity of the peritoneal membrane [124, 125]. As GDP are readily
absorbed, they may promote not only local but
also systemic formation of advanced glycosylation end products (AGE). It has been speculated
that the reduced systemic AGE load may be associated with improved preservation of RRF. Results
from controlled clinical trials and meta-analysis
identified that RRF is better preserved when PD
is performed with low-GDP fluids [124, 126–

129]. A global cohort study in children also confirmed the beneficial effect of biocompatible PD
fluid on RRF [45].


11  Preservation of Residual Renal Function in Children Reaching End-Stage Renal Disease

1.0
0.9
Proportion of patients without
oligoanuria (1 = 100%)

Fig. 11.5 Extended
preservation of residual
urine output by loop
diuretic treatment in
children undergoing
chronic PD. (Modified
from Ref. [45])

165

Diuretics

0.8
0.7

No diuretics

0.6
0.5

0.4
0.3
0.2
0.1
Log rank P = 0.041

0.0
0

6

12

18

24

30

36

42

48

Time on PD (months)

Hemodialysis
Not all, but most studies in adult patients on
hemodialysis showed that RRF was preserved

better with the use of dialyzer membranes made
of biocompatible polysulfone material than with
cellulose or cuprophane membranes [69, 96, 130,
131]. The protective effect of biocompatible
membranes may be related to the attenuated
inflammatory response induced upon exposure,
characterized by less marked activation of the
complement system and circulating leukocytes
[96, 132, 133]. It has also been reported that the
use of ultrapure water and bicarbonate buffer preserves RRF [5, 134].
In addition, high-flux membranes, hemodiafiltration, and combination of hemodialysis and PD
or hemodialysis and hemoperfusion have been
reported to improve the preservation of RRF [5,
135–138].

Emerging Therapies

that administration of N-acetylcysteine 1200  mg
twice daily preserved RRF in adult patients undergoing hemodialysis and PD [140, 141].

Special Conditions
In patients returning to dialysis after failed transplant, continued immunosuppression preserves
the residual allograft function for some time [96].
Of course, side effects of the immunosuppressive
medications have to be weighed against the benefit of RRF in these patients.
There are unusual situations when more rapid
loss of urine volume, or even nephrectomy, is
rather preferable because of refractory edema
caused by severe proteinuria and hypoalbuminemia. The information described above could
help caring for these patients in an opposite way,

for example, by administration of NSAIDs.

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