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28  Growth and Pubertal Development in Children and Adolescents Receiving Chronic Dialysis
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The Management of CKD-MBD
in Pediatric Dialysis Patients

29

Justine Bacchetta and Isidro B. Salusky

Abbreviations

Introduction

1,25D
ADHR

Children with chronic kidney disease (CKD),
especially those on dialysis, have a tenfold
increase of cardiovascular (CV) morbidity and
mortality, due to a unique combination of traditional and uremia-related risk factors, especially

disturbances of mineral and bone metabolism
parameters [1]. Pediatric CKD patients usually
do not present with the traditional risk factors for
cardiovascular disease (CVD); however, despite
our current therapies, CVD remains the leading
cause of morbidity and mortality in this patient
population [1]. The “tip of the iceberg” of these
complications is multifactorial, and multiple factors have been identified such as abnormalities in
bone and mineral metabolism, resistance to
growth hormone (GH), modifications of the
GH-insulin-like growth factor type 1 (IGF1) axis,
hypogonadism, malnutrition, and drug toxicity
(corticosteroids) [2]. Not only do these complications impact overall quality of life through their
effects on both physical and mental well-being in
children with CKD, but alterations in mineral
metabolism and bone disease also contribute to a
significant decrease in life expectancy.
Therefore, due to the complex interplay
between bone disease, mineral metabolism, and
cardiovascular disease in patients with CKD, a
new definition of renal osteodystrophy (ROD) was
proposed: indeed ROD is defined now as a systemic disorder of chronic kidney disease mineral
and bone disorder (CKD-MBD) characterized by

1,25-Dihydroxyvitamin D
Autosomal dominant hypophosphatemic rickets
ALP
Alkaline phosphatase
CKD
Chronic kidney disease

CKD-MBD Chronic kidney disease/mineral
and bone disorders
CVCardiovascular
CVD
Cardiovascular disease
DXA
Dual X-ray absorptiometry
ESRD
End-stage renal disease
FGF23
Fibroblast growth factor 23
GFR
Glomerular filtration rate
HR-pQCT High-resolution peripheral quantitative computed tomography
PTH
Parathyroid hormone
ROD
Renal osteodystrophy

J. Bacchetta (*)
Pediatric Nephrology, Rheumatology and
Dermatology Unit, Reference Center for Rare
Renal Diseases and Rare Diseases of Calcium
and Phosphate Metabolism, Hôpital Femme Mère
Enfant, Bron, France
e-mail:
I. B. Salusky
Division of Pediatrics Nephrology, Department
of Pediatrics, UCLA Mattel Children’s Hospital,
Los Angeles, CA, USA

© Springer Nature Switzerland AG 2021
B. A. Warady et al. (eds.), Pediatric Dialysis, />
541


J. Bacchetta and I. B. Salusky

542

Table 29.1  The spectrum of renal osteodystrophy according to the TMV classification, adapted from [3]
Osteomalacia (OM)
Adynamic bone (AD)
Mild hyperparathyroid-related bone disease (HPT)
Mixed uremic osteodystrophy (MUO)
Osteitis fibrosa (OF)

Turnover
Low
Low
Mild
High
High

one or a combination of the following abnormalities [3, 4]: (1) abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; (2)
abnormalities in bone histology, linear growth, or
strength; and (3) vascular or other soft tissue calcification. The term ROD refers only to the specific
abnormalities of bone diagnosed by bone histomorphometry using three main criteria, turnover,
mineralization, and volume (TMV classification),
as illustrated in Table 29.1. The impact of CKDMBD in children may occur early in the course of

CKD and is characterized by hormonal (PTH,
1,25D, and fibroblast growth factor 23, FGF23)
and biochemical (serum calcium and phosphorus
levels) abnormalities, while delayed complications (e.g., growth retardation, bone deformities,
fractures, vascular calcifications, increased morbidity and mortality) may also occur [3].The bone
and growth long-term consequences of CKD have
been highlighted in a cohort of 249 young Dutch
adults with onset of end-stage renal failure before
the age of 14 years: in this cohort, 61% of patients
had severe growth retardation, 37% severe bone
disease (as defined by at least one of the following
conditions: deforming bone abnormalities, chronic
pain related to the skeletal system, disabling bone
abnormalities, aseptic bone necrosis, and low-­
trauma fractures), and 18% disabilities resulting
from bone impairment [5]. More recently, a significantly increased risk of fractures was demonstrated in the pediatric North American CKiD
cohort, evaluating 537 children with CKD at a
median age at inclusion of 11 years. At baseline,
16% of them had a history of fractures, and after a
median follow-up of 3.9  years, 43 boys and 24
girls experienced fractures, corresponding to a
fracture risk two- to threefold higher than in general populations [6]. Moreover, risk factors were
Tanner stage IV/V, decreased height Z-score,

Mineralization
Abnormal
Normal
Normal
Abnormal
Normal

Volume
Low to normal
Low to normal
Normal to high
Normal
High

walking difficulty, and increased PTH levels. In
contrast, the only protective factor was the use
of phosphate binders, mainly calcium-based
binders [6].
Evidence of vascular calcifications has been
demonstrated in children and young adult dialysis patients with ESRD therapy initiated in childhood [7, 8]. Our understanding of the relationship
between bone and vessels in CKD remains
scarce. Associations between arterial lesions
(atherosclerosis and arterial calcifications) and
bone impairment (osteoporosis and abnormal
bone activity) are described, usually following
the rule “The better the bone, the better the vessels,” at least in adults [9, 10]; however, things
are not that clear in pediatric CKD, and using
absorptiometry (DXA) and even high-resolution
peripheral quantitative computed tomography
(HR-pQCT), opposite results were reported [11,
12].The aim of this review is therefore to provide
an overview of our current understanding of the
abnormalities of bone and mineral metabolism
associated with CKD in children undergoing
maintenance dialysis, notably in terms of diagnosis and management.

 hanges in Mineral Metabolism
C
with Progressive CKD
CKD-MBD pathogenesis involves a complex
interplay among the kidney, bone, and parathyroid glands. As functional nephrons are lost and
GFR declines, a cascade of maladaptive events
develops that result in bone disease, extra-­skeletal
calcification, and adverse cardiovascular outcomes. Different factors have been implicated in
the pathogenesis of this maladaptive response, but
the primary trigger remains to be defined. In the


29  The Management of CKD-MBD in Pediatric Dialysis Patients

early stages of CKD, FGF23 levels increase,
while phosphate, calcium, and PTH levels remain
within normal ranges [13]. With CKD progression, there are increase in phosphate levels,
increased levels of FGF23 and PTH, progressive
decline in 1,25D levels in order to lessen enteral
phosphate absorption, and decreased ionized calcium levels via increased binding. Elevated
FGF23 levels further decrease 1,25D levels via
renal
1α-hydroxylase
suppression
and
24-­hydroxylase induction. Decreased 1,25D levels reduce intestinal calcium absorption, and low
1,25D and low ionized calcium both further
increase PTH levels, resulting in secondary hyperparathyroidism, as summarized in Fig. 29.1 [14].
Since bone consists primarily of calcium and
phosphorus, in the form of hydroxyapatite, it is

not surprising that alterations in mineral metabolism, as occur with progressive CKD, lead to
bone disease. However, all these biochemical
alterations do not completely explain CKD-­

543

MBD. In 2000, a novel hormone negatively regulating phosphate, 1,25D, and PTH has been
identified, FGF23, completely modifying our
view of CKD-MBD [15–17].
Indeed, the earliest biochemical abnormality
in CKD is an increase in circulating FGF23 levels
[13, 16]. FGF23, in conjunction with its co-­
receptor, Klotho, activates FGF receptor 1
(FGFR1) and acts on the kidney to induce renal
phosphate wasting and to suppress renal
1α-hydroxylase activity [18–20]. FGF23 also
acts on the parathyroid gland and may play a role
in suppressing parathyroid hormone (PTH) levels
[21]. FGF23 is stimulated by phosphate and
1,25(OH)2vitamin D, and, in both adults and children, FGF23 increases as GFR decreases, with
elevations in circulating and bone levels occurring in very early stages of CKD, prior to any
apparent alterations in circulating mineral content [22]. This increase could be explained by different factors, including a decreased renal

1-25 vitamin D

Phosphate

Calcium

FGF23 /

Klotho

PTH

Stimulating effect / Inhibiting effect

Fig. 29.1 Overview of normal phosphate/calcium
metabolism. Phosphate and calcium are mainly stored in
bone, but the gut and the kidneys have a key role in their
homeostasis. Three hormones are crucial to maintain calcium and phosphate within the normal range:

1,25-­dihydroxyvitamin D (1,25D), parathyroid hormone
(PTH), and fibroblast growth factor 23 (FGF23). Green
lines correspond to a stimulating effect. Red lines correspond to an inhibitory effect


J. Bacchetta and I. B. Salusky

544

clearance of FGF23, a compensatory mechanism
to excrete an increased phosphate load, a response
to treatment with active vitamin D analogs, and/
or a compensatory mechanism to the loss of the
kidney-secreted Klotho protein. However, the
initial factor that triggers FGF23 production
remains to be defined. Data from CKiD nevertheless argue against the first hypothesis, since at the
very early stages of pediatric CKD, circulation
and bone FGF23 levels are already increased,
whereas phosphate SDS are significantly

decreased [13]. Although these increased circulating levels of FGF23  in CKD patients consist
almost exclusively of the intact, active form of
the molecule, it is not clear whether the biological effects of FGF23 are increased or decreased
in the context of decreased kidney function.
Indeed, decreased expression of FGFR1 and
Klotho in parathyroid cells from dialysis patients

and a resistance to the suppressive effects of
FGF23 on PTH in uremic rats suggest that FGF23
signaling to the parathyroid glands is downregulated in CKD and may explain, at least in part, the
refractory
secondary
hyperparathyroidism
observed in CKD patients.
Over the last decade, the extra-skeletal and systemic effects of FGF23 have been well characterized in adults and children, highlighting a global
“negative” role of FGF23  in global health [14],
notably on the cardiovascular, immune, and central nervous systems, as illustrated in Fig.  29.2.
The first “off-target” effect of FGF23 to be
described was demonstrated on cardiomyocytes
[23]. This seminal paper was a milestone in the
understanding of FGF23 physiology since it was
the first time that a Klotho-independent effect of
FGF23 was demonstrated, with different downstream phosphorylation pathways, mainly the cal-

Heart &
Cardiomyocytes

Kidney
Saito, J Biol Chem 2003
Andrukhova, EMBO 2014

Faul, JCI 2011;
Leifheit-Nestler NDT 2018

Hippocampal cells
and CNS

Parathyroid

Hensel, J Neurochem 2016
Silver, PN 2010
Olauson Plos One 2013

Hematopoiesis
FGF23
Hanudel AmJPhysiol2016,
NDT 2018

Immune system

Hepatocytes

Bacchetta, JBMR 2012
Chonchol, JASN 2015 & JASN 2016

Singh Kidney Int 2016

Bone
Cartilage
Kawai, JBC 2013

Wang JBMR 2008, Wesseling
Perry JCEM 2009, Allard CTI
2015

Dentoalveolar complex
Chu, Anat Rec 2010

Fig. 29.2  Systemic effects of FGF23, adapted from [14].
Besides its “classical” effects on phosphate, calcium,
PTH, and vitamin D metabolism, the knowledge in FGF23
physiology has dramatically improved recently. Complex

regulations between FGF23 and all these systems have
been described; the relevant papers are referenced on the
figure, but this list is not exhaustive