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28  Growth and Pubertal Development in Children and Adolescents Receiving Chronic Dialysis

Nevertheless, patients who demonstrate delayed
puberty  – that is, boys with a testicular volume
<4 ml at the age of 14 years and girls with breast
stage to a pediatric endocrinologist for full workup and
potential induction of puberty [22].

Pubertal Growth
During the last two decades, in parallel with
the improvement in sexual maturation has been
an improvement in pubertal height gain [5, 9,
23, 29]. Longitudinal growth in 384 German
children on RRT who were followed between
1998 and 2009 was compared with 732 children
enrolled in the European Dialysis and Transplant
Association (EDTA) registry between 1985 and
1988 (Fig. 28.5) [9]. In line with previous studies, the pubertal growth spurt in the patients in
the earlier EDTA study was delayed by approximately 2.5 years. In many of these patients, no
clear pubertal growth spurt was present, and
consequently standardized height decreased
during pubertal age. In contrast, a clear pubertal growth spurt was present, and the onset of
the pubertal growth spurt was within the normal range in the majority of patients followed
up more recently. Consequently, standardized
height even improved during puberty and until
adult height. Thus, whereas 20 years ago a loss
of about 1.0 SD was expected during puberty,
currently a normal or only slightly reduced
pubertal growth spurt can be expected if longterm dialysis is avoided.
Segmental Growth

It has been postulated that during malnutrition
there is preferential preservation of growth of
vital organs at the expense of less vital tissues
such as the limbs, so that malnutrition during
childhood results in disproportionate stunting
with impairment of leg growth and preserved
trunk and head growth [44]. To that end, relative
leg length is increasingly used as a biomarker of
childhood nutrition in epidemiological studies
[45–47]. Information pertaining to segmental
growth has been collected in the CKD Growth
and Development Study, a study in which more

515

than 800 pediatric CKD patients before and after
transplantation have been enrolled since 1998.
Patients undergo yearly detailed anthropometric
assessments at two pediatric nephrology centers
in Northern Germany in this prospective observational study. Patients with a long-term history of
CKD and RRT demonstrated an age-related disproportionate growth pattern [3, 4, 48]. Growth
impairment and disproportionality was most
obvious in early childhood. Sitting height was
mostly preserved, whereas growth of the legs and
arms was most severely affected (Fig.  28.6a).
This resulted in a markedly elevated sitting height
index (ratio of sitting height to total body height).
Leg length was more affected in prepubertal
compared to pubertal patients. Consequently,
body disproportion was less pronounced in

pubertal patients. In addition to transplant function and steroid exposure, congenital CKD, small
for gestational age, young age, and use of rhGH
in the pre-transplant period were significantly
associated with growth outcome (stature and
degree of body disproportion) in these patients.
Noteworthy was the finding that kidney transplantation resulted in complete normalization of
body proportions until attainment of adult height
in the vast majority of patients affected
(Fig. 28.6b) [4].

 tiology of Growth Failure
E
in Chronic Kidney Disease
There is no single cause of growth failure in
CKD (Table  28.1). Children may suffer from
various acquired or congenital renal abnormalities, manifesting in early or late childhood and
differing widely with respect to severity and
rate of progression. Likewise, a broad spectrum of concomitant complications (e.g., metabolic acidosis, electrolyte disturbances, and
malnutrition) has to be considered (Fig.  28.2).
Furthermore, children with CKD may undergo
various therapeutic interventions and different
modes of renal replacement therapy of variable timing and duration during their growth
period. While some factors, such as nutritional


D. Haffner and J. D. Mahan

516
Fig. 28.5 (a) Mean
height velocity of

European children with
renal replacement
therapy in the EDTA
study 1985–1988 (blue
lines) versus the
Hannover/Berlin (H/B)
pediatric population
cohort 1998–2009
(orange lines) in
different age cohorts.
(Reproduced with
permission of Ref. [9]).
(b) Age-dependent
height standard
deviation score of
European children on
renal replacement
therapy 1985–1988
(EDTA study, n = 732,
blue error bars) and in
the HB group (n = 384,
orange error bars).
EDTA, European
Dialysis and Transplant
Association, CI
confidence interval.
(Reproduced with
permission of Ref. [9])

a

b


28  Growth and Pubertal Development in Children and Adolescents Receiving Chronic Dialysis
Fig. 28.6 (a) Mean SD
scores (SDS) for stature,
sitting height, and arm
and leg lengths in 389
patients who had
received transplants. (b)
Mean sitting height
index (ratio between
trunk length and total
body height) as a
function of age in 389
renal transplant
recipients. *P < 0.05 for
age cohorts of 3 years
versus 5 years;
**P < 0.05 for age
cohorts of 2–5 years
versus 8–12 years;
***P < 0.05 for age
cohorts of 8–12 years
versus 14–18 years.
Data are given as mean
and 95% confidence
interval. Horizontal lines
refer to the normal mean

(0 SDS) and lower (−2.0
SDS) and upper (2.0
SDS) normal range.
(Reproduced with
permission of Ref. [4])

517

a

b

and hormonal abnormalities, and hematological and metabolic derangements, such as acidosis, electrolyte imbalance, CKD-MBD, and
anemia, are potentially correctable, the effects
of others, such as birth parameters, associated
syndromes, and parental heights, are not [49].
In addition, differences in economics (based

on gross national income) and socioeconomic
status substantially impact growth outcome in
various countries. The effect of these economic
factors has been shown to be independent of
well-known factors that impair growth such as
congenital CKD, anuria, and dialysis vintage, as
outlined below [18].


518
Table 28.1  Factors that contribute to growth failure in
children with CKD

Genetic factors
 Parental heights
 Gender
 Syndromic kidney diseases
Birth-related factors
 Prematurity
 Small for gestational age
 Intensive care requirement
Comorbidities (e.g., central nervous system, liver, or
heart involvement)
Age at onset of CKD
Severity of CKD and residual renal function in
patients on dialysis
Anemia
Metabolic disturbances
 Salt and water metabolism
 Metabolic acidosis
 CKD-MBD
Malnutrition
 Altered taste sensation
 Anorexia
 Vomiting
 Dietary restrictions
 Nutrient losses in dialysate
 Infections and inflammation
Protein-energy wasting
 Infections and inflammation
 Uremic toxins
 Oxidative stress
 Inflammatory cytokines

Hormonal disturbances affecting:
 The somatotropic hormone axis
 The gonadotropic hormone axis
 PTH and vitamin D metabolism or action
 Gastrointestinal hormones
Reproduced with permission of Ref. [22]
CKD chronic kidney disease, MBD mineral and bone disorder, PTH parathyroid hormone

Underlying Renal Disease
Congenital anomalies of the kidneys and urinary
tract (CAKUT), characterized by renal hypoplasia or dysplasia with and without reflux or
obstructive uropathy, are the most common
causes of ESKD during infancy and childhood.
Renal dysplasia is often associated with electrolyte and/or water losses, and losses of both are
likely to contribute to growth failure [50]. Thus,

D. Haffner and J. D. Mahan

it is important to compensate for these losses and
to provide appropriate treatment of concomitant
urinary tract infections as part of successful
growth management.
In children suffering from glomerulopathies,
growth rates might decline even with rather mild
renal insufficiency. The nephrotic state per se and
glucocorticoid treatment are known risk factors
for growth delay [51]. Congenital nephrotic syndrome is usually associated with severe early
infantile growth failure, which may occur even
with preserved global renal function. The poor
growth seems to be secondary to persistent

edema, recurrent infections, losses of peptide and
protein-bound hormones, and/or protein-calorie
malnutrition [52, 53]. In Finnish-type congenital
nephrotic syndrome, aggressive nutritional support is vital, and bilateral nephrectomy and initiation of peritoneal dialysis may be necessary to
improve growth. In other types of congenital
nephrotic syndrome, unilateral nephrectomy and
treatment with prostaglandin synthesis inhibitors
and renin-angiotensin system (RAS) antagonists
can reduce proteinuria and thereby improve
growth and the overall clinical condition [52, 54].
Nephropathic cystinosis results in complex
tubular dysfunction and is associated with severe
growth failure early in infancy, even when glomerular function is not yet compromised [55,
56]. Progressive growth failure is further augmented in these children by generalized deposition of cystine crystals altering the function of
growth plates, bone marrow, hypothalamus, pituitary gland, and thyroid gland. However, early
initiation of treatment with the cystine-depleting
agent cysteamine improves growth and delays
the development of ESKD by approximately
10  years [55, 57]. Consequently, height at the
start of RRT in this population has significantly
improved during the last decade [58]. In patients
with primary hyperoxaluria, supplementary treatment with citrate and pyridoxine can delay progression of renal failure and possibly improve
longitudinal growth [59]. In patients with systemic oxalosis, combined liver and kidney transplantation is a curative option; however, real
catch-up growth after combined transplantation
is rarely observed, even in prepubertal oxalosis


28  Growth and Pubertal Development in Children and Adolescents Receiving Chronic Dialysis

patients [28]. Most important is the recognition

that every measure directed to preserve kidney
function except glucocorticoid therapy has a beneficial impact on growth in children with CKD.

519

sis patients and may also lead to GH insensitivity and growth failure in children on dialysis
[63–66]. Indeed, an in vitro study demonstrated
that uremia attenuates GH-stimulated insulinlike growth factor I (IGF-I) expression in the
liver, which was further aggravated by inflamConsequences of Renal Disease
mation [63].
There is no consensus about how to determine
Protein-Calorie Malnutrition
the degree of severity of MICS or how to manage
Nutritional imbalances, particularly protein-­ it. Anorexia manifests early in the course of renal
energy malnutrition, are frequently seen in chil- failure and usually progresses with declining
dren suffering from CKD.  Infants and young renal function [38]. In addition, protein synthesis
children are particularly vulnerable to malnutri- is decreased in uremia, and catabolism is increased
tion because of low nutritional stores and high [67]. In CKD patients, spontaneous energy intake
energy demands which are, in turn, necessary to is directly correlated with decreased growth if it is
achieve high growth rates in this age group [20, less than 80% of recommended dietary allowance
32, 60]. Anorexia in CKD is due to a combination [68]. Unfortunately, further augmentation of
of altered taste sensation, decreased clearance of energy above 100% of recommended dietary
cytokines that affect appetite and satiety, obliga- allowance tends to result in obesity rather than
tory losses of salt and water leading to preference additional length/height gain [69–72]. Other
for salty foods and large volumes of water, and approaches to prevent MICS may include the
the need for multiple medications. Vomiting is preferential use of biocompatible dialysis matericommon, particularly in infants. PD results in als to minimize inflammatory responses and
raised intra-abdominal pressure, which may also intensified dialysis protocols to increase cytokine
have an adverse effect on appetite and cause clearance and improve volume status. Preliminary
vomiting. Malnutrition is a crucial clinical issue results support the efficacy of these measures in
since it is also significantly associated with improving growth hormone sensitivity and inducincreased mortality in children suffering from ing catch-up growth (see below).

CKD [14–16].
The term malnutrition-inflammation com- Metabolic Acidosis
plex syndrome (MICS) has been coined to Metabolic acidosis (serum bicarbonate <
describe the association between chronic inflam- 22 mEq/l) usually occurs when the GFR is below
mation and malnutrition in dialyzed children 50% of normal, although nutritional intake (proand adults. Another term, protein-energy wast- tein and acid load), catabolism, and alterations in
ing (PEW), was also recently coined which electrolyte balance contribute to its development.
more or less describes the same pathophysiolog- Subsequent metabolic and endocrine aberrations
ical scenario [61, 62]. Possible causes of MICS/ are triggered by metabolic acidosis and aggravate
PEW include comorbid illnesses, oxidative and uremic growth failure. In fact, metabolic acidosis
carbonyl stress, nutrient loss through dialysis, is significantly associated with decreased length
anorexia and low nutrient intake, uremic toxins, gain and increased protein breakdown in children
cytokine induction by exposure to bio-­ with CKD [73–75]. Studies on metabolic acidosis
incompatible dialysis materials, decreased in uremic animals have revealed a complex patclearance of inflammatory cytokines, volume tern of interrelated pathophysiological ­reactions.
overload, and other dialysis-related factors. Metabolic acidosis increases glucocorticoid proMICS may contribute to erythropoietin hypore- duction and protein degradation while concomisponsiveness, early cardiovascular atheroscle- tantly suppressing spontaneous pituitary GH
rotic disease, decreased quality of life, and secretion, decreasing expression of the GH recepincreased mortality and hospitalization in dialy- tor and IGF-I receptor, and decreasing IGF-I


520

serum concentrations; these effects highlight the
necessity for adequate control of metabolic acidosis in children with CKD [76, 77]. Likewise, metabolic acidosis was noted to be undertreated in the
CKiD population and associated with poor growth
which further supports the concept that interventions targeting metabolic acidosis may improve
growth in this population [40].

 KD-Mineral and Bone Disorder
C
(CKD-MBD)
It is widely accepted that skeletal deformities due
to CKD-MBD can contribute to uremic growth

failure [78, 79]. Pronounced secondary hyperparathyroidism (sHPT) can interfere with longitudinal growth by destruction of the growth plate
architecture, epiphyseal displacement, and
metaphyseal fractures. Severe destruction of the
metaphyseal bone architecture may result in
complete growth arrest. Although treatment with
1,25-dihydroxyvitamin D3 (1,25(OH)2D3) reverts
sHPT and improves growth in uremic rats, this
has not been demonstrated in children with CKD
[80–82]. The situation is even more complicated
since skeletal growth is the net result of proliferation and differentiation of growth plate chondrocytes with subsequent mineralization of the
extracellular matrix. According to current knowlFig. 28.7 Time-­
averaged mean plasma
intact parathyroid
hormone (iPTH)
concentrations and
change in standardized
height in 214 pre- and
early pubertal children
on peritoneal dialysis
followed prospectively
for at least 12 months.
Full circles indicate
patients receiving
recombinant human
growth hormone.
(Reproduced with
permission of Ref. [89])

D. Haffner and J. D. Mahan

edge, this biological process is under the control
of three hormones, namely, PTH, 1,25(OH)2D3
(calcitriol), and fibroblast growth factor 23
(FGF23), as well as numerous paracrine and
autocrine signals [83].
The contribution of sHPT to uremic growth
failure has not been fully elucidated. Under physiological conditions, growth plate chondrocytes
proliferate and differentiate under the influence of
PTH, mainly mediated by the induction of local
IGF-I synthesis [84]. However, bones and growth
plates are relatively resistant to PTH in chronic
uremia [85]. Hence, low or normal PTH levels,
which are indicative of low bone turnover in
experimental uremia as well as in children with
CKD stage 5D, have been suspected to impair
longitudinal growth [86]. However, low bone
turnover is rarely seen in children on dialysis
(approx. 4%) [87]. In addition, one well-­designed
direct histomorphometric assessment in children
on dialysis showed no association between low
bone turnover and statural growth [88].
The IPPN offers the most up-to-date information pertaining to the association between PTH
and growth in a large cohort of pediatric PD
patients. The annual prospective change in standardized height of this patient cohort tended to
correlate inversely with time-integrated mean
PTH levels (Fig. 28.7): patients with mean PTH
levels >500  pg/ml (i.e., >9 times upper limit of