Chest configuration in children and adolescents with infantile nephropathic cystinosis compared with other chronic kidney disease entities and its clinical determinants

Abstract

Background:
Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk.

Methods:
Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models.

Results:
Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years).

Conclusion:
Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.

Full text

Vol.:(0123456789)
1 3
Pediatric Nephrology
https://doi.org/10.1007/s00467-023-06058-x
ORIGINAL ARTICLE
Chest configuration inchildren andadolescents withinfantile
nephropathic cystinosis compared withother chronic kidney disease
entities andits clinical determinants
SophiaMüller1· RikaKluck1· CelinaJagodzinski1· MalinaBrügelmann1· KatharinaHohenfellner2·
AnjaBüscher3· MarkusJ.Kemper4· KerstinFröde1· JunOh5· HeikoBilling6· JuliaThumfart7· LutzT.Weber8·
BirgitAcham‑Roschitz9· KlausArbeiter10· BurkhardTönsho11· MartinaHagenberg12· LeoPavičić13·
DieterHaner1· MiroslavZivicnjak1
Received: 13 March 2023 / Revised: 9 June 2023 / Accepted: 13 June 2023
© The Author(s) 2023
Abstract
Background Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine
accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy.
An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the function-
ality of the trunk.
Methods Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in
44 pediatric patients with INC with CKD stages 1–5 and 97 age-matched patients with CKD of other etiology between the
ages of 2–17years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed,
and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models.
Results Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by mark-
edly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD
were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from
2–6years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree
of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2–6, 7–12,
and 13–17years).
Conclusion Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from
CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage,
which are associated with kidney function.
Keywords Infantile nephropathic cystinosis· Chest· Biacromial diameter· Anterior–posterior chest diameter· Chronic
kidney disease· Fanconi syndrome
Introduction
Infantile nephropathic cystinosis (INC) is a lysosomal stor-
age disease causing multisystem intracellular cystine crystal
accumulation and ensuing multisystem complications, often
first affecting the kidney [1–3]. Symptoms due to generalized
proximal tubule dysfunction (Fanconi syndrome), i.e., poly-
uria, failure to thrive and hypophosphatemic rickets, typi-
cally manifest within the first 18months of life, followed by
progressive chronic kidney disease (CKD) and a multitude
of other complications including malnutrition, myopathy,
and endocrine dysfunction [1, 2, 4–6]. Myopathy and asso-
ciated respiratory dysfunction are frequent features in older
patients with INC, with reported aberrations in chest shape
in affected patients [7–9].
Despite adequate treatment of Fanconi syndrome and
cystine depleting therapy, which was shown to delay the
need for kidney replacement therapy, children with INC
Sadly, Heiko Billing passed away before the completion of this
work. since the research was initiated with his contribution, the
authors decided to submit his name as co-author.
Extended author information available on the last page of the article

Pediatric Nephrology
1 3
are prone to progressive disproportionate short stature [10,
11]. This is characterized by a shift from a trunk length
preserving pattern shared with children with CKD of other
causes to an INC-specific leg-focused growth pattern [10],
prompting further examination of the morphology of the
trunk of INC patients.
Biacromial diameter, for one, is known to be linked
to quality of living conditions or level of physical
activity [12, 13], and the ribcage, on the other hand,
can be influenced through rickets [14], which is a
hallmark in INC patients [1, 4, 5]. Thus, we hypoth-
esized that children with INC present with character-
istic changes of the aforementioned dimensions when
compared to their peers with CKD. To test this, we
prospectively investigated thoracic dimensions and
proportions, i.e., chest depth/height and chest depth/
chest width ratios, in conjunction with detailed bio-
chemical parameters. Those were assessed in a cohort
of pediatric patients with INC with CKD stages 1–5
and matched CKD controls with other hereditary or
congenital kidney diseases across three age groups
(ages 2–6, 7–12, and 13–17years).
Material andmethods
Study design andpatients
This analysis includes children with INC and hereditary or
congenital CKD aged 2 to 17years with CKD stages 1–5
only prior to kidney replacement therapy who are enrolled
in the prospective multicenter observational cohort study
“Growth and cognitive-motor abilities in children with
nephropathic cystinosis and chronic kidney disease” [10,
15]. Patients with complex or syndromic diseases were
excluded. Between January 2016 and January 2022, a total
of 44 patients with INC and 97 age-matched CKD controls
from thirteen pediatric centers across Germany and Aus-
tria were eligible for analysis. Underlying kidney diseases
in the CKD control group included congenital anomalies of
the kidney and urinary tract (CAKUT, 64.9%), nephronoph-
thisis (3.1%), autosomal recessive polycystic kidney dis-
ease (ARPKD, 6.2%), and other causes of CKD (23.7%).
The mean patient age was 9.94years in patients with INC
(95% CI 9.09–10.78) and 9.13 in CKD controls (95% CI
8.57–9.70; Table1). Patients were annually assessed
Table 1 Patient characteristics
and treatment in 44 children
with infantile nephropathic
cystinosis with CKD stages 1–5
and 97 CKD controls
N describes the number of either patients (for static patient dependent characteristics, signified with *) or
yearly measurements (for repeated clinical measurements and medication) out of overall valid patient cases
or valid yearly measurements, i.e. without separation into age subgroups
CKD chronic kidney disease, n.a. not applicable, SGA small for gestational age
INC CKD p-value
Incidence % NIncidence % N
Male sex 54.5 24 of 44* 67.0 65 of 97* 0.188
Congenital CKD – – 89.7 87 of 97* n.a
SGA history 18.2 6 of 33* 20.7 17 of 82* 1.000
Metabolic acidosis 40.5 30 of 74 36.2 77 of 213 0.577
Hypokalemia 44.8 39 of 87 4.4 9 of 206 0.000
Hypophosphatemia 21.7 18 of 83 2.4 5 of 208 0.000
Hypocalcemia 60.8 48 of 79 35.6 74 of 208 0.000
Anemia 15.7 14 of 89 26.0 57 of 219 0.054
Medication
Erythropoietin 20.2 18 of 89 25.9 55 of 212 0.307
Iron 21.3 19 of 89 30.2 64 of 212 0.123
Active vitamin D 50.6 45 of 89 33.5 71 of 212 0.006
Native vitamin D 74.2 66 of 89 72.6 154 of 212 0.887
Bicarbonate 70.8 63 of 89 47.2 100 of 212 0.000
Potassium 79.8 71 of 89 1.9 4 of 212 0.000
Calcium 12.4 11 of 89 1.9 4 of 212 0.000
Phosphate 66.3 59 of 89 1.9 4 of 210 0.000
Carnitine 53.4 47 of 88 0.0 0 of 213 0.000
Antihypertensives 27.0 24 of 89 57.1 124 of 217 0.000
Growth hormone 52.3 23 of 44* 25.8 25 of 97* 0.004
Cysteamine 100.0 91 of 91 – n.a

Pediatric Nephrology
1 3
including physical examination, history of medication, rou-
tine biochemical parameters, and detailed anthropometric
assessment. All patients regularly received dietary advice
by a dietician to ensure adequate caloric and protein intake.
Appropriate Ethics Committee approval was obtained
from the institutional review boards at each study site, and
this study was performed in accordance with the Declaration
of Helsinki. Written informed consent was obtained from all
parents/guardians, with consent or assent from patients when
appropriate for their age.
Methods
Yearly anthropometric assessments were performed according to
the International Biological Program recommendations and per-
formed by the same investigator (M.Ž.) with standardized equip-
ment as previously described [16–18]. An average of 2.22 yearly
measurements were performed per patient, including height and
thoracic parameters, i.e., biacromial diameter (shoulder width),
anterior–posterior (AP) chest diameter (chest depth), and trans-
verse chest diameter (chest width). This was used to calculate
chest depth/height ratio (APC-height ratio, i.e.
APC in mm
height in mm
×
100
)
and chest depth/chest width ratio (APC-transverse chest ratio, i.e.
APC in mm
transverse chest diameter in mm
×
100
), as measures of chest propor-
tion. From those parameters and ratios, age- and sex-dependent
z-scores were calculated using anthropometric parameters from
reference data derived from healthy children [17, 18],
(e.g.
(patient APC height ratio −mean APC height ratio of reference group)
standard deviation of APC height ratio of reference group
=APC −
height ratio z score
).
Information regarding current biochemical parameters
and medication was obtained at each anthropometric meas-
urement appointment. Standard laboratory techniques were
used for the measurement of serum concentrations of cre-
atinine, urea, calcium, phosphate, potassium, albumin,
bicarbonate, intact parathyroid hormone (PTH), and hemo-
globin blood levels. Serum calcium levels were corrected
regarding albumin [19]. Estimated glomerular filtration
rate (eGFR) was calculated by use of the revised Schwartz
equation [20]. Intracellular leukocyte cystine levels were
measured at laboratories of Hanover Medical School and
the University Children’s Hospital Muenster [21, 22] and
uniformly converted to nanomoles half-cystine per milli-
gram protein. Age- and sex-dependent reference intervals
were used for determining frequencies of hypokalemia,
hypophosphatemia, hypocalcemia, and anemia. Meta-
bolic acidosis was defined by presence of serum bicarbo-
nate < 22mmol/L [23–26].
Information from patients’ standardized pregnancy and
birth health care booklets was used to classify patients born
small for gestational age (SGA), i.e., if birth weight and/or
birth length were below the 10th percentile when compared
to the respective gestational age and sex of national birth
and growth data [27].
Statistical analysis
Data presentation in yearly age cohorts (e.g., age
2 = 2.00–2.99years) was not feasible due to the low number
of patients. Therefore, patients’ measurements were divided
into three age groups: (i) ages 2–6years (109 total measure-
ments, 77 CKD, 32 INC), (ii) ages 7–12years (129 measure-
ments, 100 CKD, 29 INC), and (iii) ages 13–17years (75
measurements, 44 CKD, 31 INC). These age ranges reflect
relevant stages of biological development, i.e., early child-
hood, mid-late childhood, and adolescence, and account
for the usually slightly delayed onset of puberty in CKD
patients [28]. The separation of repeated patient measure-
ments into the age groups results in some patients being
measured multiple times in the same age group and across
different age groups. To adjust for the amount each patient
was measured in each age group, adjustments were made to
the linear mixed-effects models (see below).
Differences in categorical variables (i.e., incidence)
between groups (CKD vs. INC) were analyzed using the
chi-square test or Fisher’s test of significance, as appropriate.
Data distribution normality of continuous data with non-
repeated measurements was evaluated using the Kolmogo-
rov–Smirnov test with and without Lilliefors correction and
the Shapiro–Wilk test. For comparison of continuous vari-
ables between two groups, either the t-test or Mann–Whitney
test were used, as appropriate. Linear mixed-effects models
(MIXED procedure in SPSS) were used.
Descriptive data are displayed as appropriate, as either
mean with 95% confidence interval (CI), median with
interquartile range (IQR), number of data points that dis-
play respective characteristic (n) with percentage of overall
measurements, or estimated marginal mean with 95% CI for
repeated measurements.
To assess differences between patients with CKD and
INC across all age groups for parameters with repeated
measurements, linear mixed-effects models were used.
The same method was also used to analyze the difference
in anthropometric and clinical parameters between patient
groups separately for the three age groups. Differences
between different age groups within the same patient group
(CKD or INC) were analyzed using pairwise comparison
with linear mixed-effects models.
Linear mixed-effects models were further used to ana-
lyze the association of clinical parameters (covariates) with
APC-height ratio and APC-chest transverse ratio separately
for both patient groups. The following clinical parameters
were defined as covariates: serum phosphate, calcium, potas-
sium, HCO3, intact parathyroid hormone (PTH), hemo-
globin blood levels, and estimated glomerular filtration rate
(eGFR). For graphical representation, linear mixed-effects
models were used to calculate predicted values from the
repeated measurements, adjusted for multiple comparisons.

Pediatric Nephrology
1 3
For the youngest INC age group (2–6years), linear mixed-
effects models were used to perform an analysis of APC-
height ratio z-scores and their association with eGFR nested
with patient age. For all linear mixed-effects model analyses,
different covariate structure models were tested and the most
appropriate model was chosen according to information
criteria for each analysis and group of parameters. Results
were considered significant at a level of p < 0.05. SPSS for
Windows, version 27.0 (IBM Corporation, NY, USA), was
used. Graphs were generated using GraphPad Prism 9.0.0
(GraphPad Software, Inc., San Diego, CA).
Results
Patient characteristics
The characteristics of 44 patients with INC and 97 controls
with CKD are given in Tables1 and 2. The mean age and
sex distribution did not differ between patients with INC
and CKD, either across all age groups or for individual age
subgroups (each p > 0.05). Patients with INC were diag-
nosed at a median age of 1.04years (IQR 0.7, 2.1), and
all received cysteamine treatment with a median dosage
of 1.3g/m2 body surface area (IQR 1.02, 1.68) at the time
of their most recent measurement, which was started at a
median age of 1.22years (IQR 0.93, 2.48). Median leuko-
cyte cystine levels of all patients with INC were 0.29nmol
half-cystine per milligram protein (IQR 0.15, 0.52). Anti-
hypertensives were used more frequently in CKD controls
(each p < 0.01, Table1), as were erythropoietin (25.9% CKD
vs. 20.2% INC) and iron substitution (30.2% CKD vs. 21.3%
INC), though not significantly. Patients with INC received
treatment with recombinant human growth hormone (rhGH)
more frequently, as well as medication to correct the conse-
quences of Fanconi syndrome, including supplementation of
potassium, calcium, and phosphate, as well as bicarbonate
and active vitamin D (each p < 0.01). Despite this, patients
with INC showed significantly lower mean serum levels of
potassium, calcium, and phosphate, as well as higher rates
of hypokalemia, hypocalcemia, and hypophosphatemia
compared to CKD controls (each p < 0.01, Tables1 and 2).
When evaluating all observed patients (2–17years), mean
eGFRcr was significantly lower in CKD controls compared
to patients with INC (48mL/min/1.73 m2 (95% CI 44–52)
versus 66mL/min/1.73 m2 (95% CI 60–72), p < 0.001), as
were hemoglobin levels (12.46g/dL (95% CI 12.28–12.65)
versus 12.9g/dL (95% CI 12.52–13.28), p < 0.05; Table2).
Age‑related changes inanthropometric parameters
Across all age groups, thoracic depth (anterior–posterior
chest diameter) and width (transverse chest diameter) sig-
nificantly differed between patients with INC and CKD con-
trols, as thoracic depth z-scores were consistently increased
(each p < 0.001) in patients with INC compared to CKD con-
trols, while thoracic width was consistently decreased (each
p < 0.01), resulting in a pronounced chest disproportion as
opposed to the more homogenous z-scores observed in CKD
controls (Fig.1). Similarly, shoulder width (biacromial
Table 2 Age distribution and biochemical parameters in 44 children with infantile nephropathic cystinosis and 97 CKD controls
N describes the number of valid measurements for respective parameter out of overall patient measurements, i.e., across all age subgroups.
Repeated measurements per patient were evaluated in linear-mixed models
INC CKD
Repeated measurements Estimated marginal mean
(95% CI)
Min.–Max NEstimated marginal mean
(95% CI)
Min.–Max N p-value
Mean age, years 9.94 (9.09–10.78) 2.28–17.90 9 9.13 (8.57–9.70) 2.09–17.93 221 0.121
Cohort 2–6 yrs 4.95 (4.28–5.63) 2.28–6.99 32 4.57 (4.11–5.02) 2.09–6.96 77 0.342
Cohort 7–12 yrs 9.82 (9.02–10.63) 7.33–12.82 29 10.02 (9.60–10.44) 7.00–12.99 100 0.649
Cohort 13–17 yrs 15.21 (14.54–15.88) 13.05–17.90 31 15.15 (14.65–15.65) 13.08–17.93 44 0.881
eGFR, mL/min per 1.73 m265.84 (59.70–71.98) 6.58–137.67 91 47.89 (44.08–51.70) 9.01–144.87 220 0.000
HCO3, mmol/L 22.84 (22.34–23.34) 16.7–29.20 74 22.86 (22.56–23.17) 16.70–30.00 213 0.946
Hemoglobin, g/dL 12.90 (12.52–13.28) 8.10–17.90 89 12.46 (12.28–12.65) 8.00–17.80 219 0.042
Sodium, mmol/L 139.86 (139.21–140.52) 132.00–151.00 90 140.41 (140.10–140.71) 133.00–149.00 219 0.136
Potassium, mmol/L 3.89 (3.78–3.99) 2.37–5.84 91 4.54 (4.47–4.61) 3.27–5.92 219 0.000
Calcium, mmol/L 2.28 (2.25–2.31) 1.84–2.55 79 2.37 (2.36–2.39) 1.90–2.97 208 0.000
Calcium, z-score − 0.88 (− 1.12 to − 0.64) − 4.74–1.40 79 − 0.08 (− 0.24–0.07) − 4.95–4.87 208 0.000
Phosphate, mmol/L 1.32 (1.27–1.38) 0.67–2.39 83 1.46 (1.43–1.50) 0.92–2.11 208 0.000
Phosphate, z-score − 1.10 (− 1.47 to − 0.73) − 4.49–5.16 83 − 0.49 (− 0.66– − 0.33) − 3.08–3.14 208 0.003
PTH, ng/L 106.61 (77.69–135.54) 4.10–623.40 81 97.35 (87.69–107.02) 5.10–607.92 196 0.548

Pediatric Nephrology
1 3
diameter) was likewise lower in patients with INC com-
pared to CKD controls and reached the level of statistical
significance at ages 7–12 and 13–17years (each p < 0.001).
In general, the degree of chest disproportion was more pro-
nounced in patients with INC compared to CKD controls,
irrespective of age. Thoracic disproportion in patients with
INC is further evidenced by markedly increased z-scores
for APC-height and APC-transverse chest diameter ratios
(Fig.2). Both ratio z-scores were significantly higher in
patients with INC compared to CKD controls, starting in
the youngest age group (2–6years) and across all observed
age groups (each p < 0.05; Fig.2).
Standardized APC-height ratio was the parameter that
most intensely distinguished patients with INC and CKD in
the youngest group (INC 2.06 z-score vs. CKD 0.25 z-score;
p < 0.001) and reached its maximum at 7–12years (INC
2.26 z-score vs. CKD 0.69 z-score; p < 0.001). Afterwards,
standardized APC-height ratio in INC patients signifi-
cantly decreased (p < 0.001), as overall height z-scores in
INC patients significantly increased from the 7–12- to the
13–17-year-old age group (p < 0.01). Hence, in the oldest
group, APC-transverse chest ratio z-scores differed more
intensely between groups (INC 1.80 z-score vs. CKD 0.36
z-score; p < 0.001), after exhibiting a continuously signifi-
cant increase across from each age group to the next and
overall, from youngest to oldest group (each p < 0.05). Taken
together, standardized APC-height ratio appeared to be the
most sensitive measure of thoracic disproportion in early
childhood, whereas standardized APC-transverse chest
ratio steadily increased into late adolescence. Although
z-scores of both observed measures of thoracic disproportion
remained markedly lower in CKD controls compared to INC
patients (each p < 0.05), both exhibited a similar develop-
ment across age groups with a maximum APC-height ratio
Fig. 1 Mean z-scores of biacromial diameter (circle), anterior–poste-
rior chest diameter (square), and transverse chest diameter (triangle)
of 44 patients with infantile nephropathic cystinosis (INC) and 97
CKD controls. Data are presented for three age cohorts (2–6, 7–12,
and 13–17 years) as age- and sex-dependent z-scores. Error bars
represent 95% confidence intervals. Dotted lines are for illustrative
purposes only, representing changes in patterns between the three
observed parameters
Fig. 2 Mean z-scores of anterior–posterior chest / height ratio (APC-
height ratio; circle) and anterior–posterior chest / transverse chest
ratio (APC-transverse chest ratio; square), and body height (triangle)
of 44 patients with infantile nephropathic cystinosis (INC) and 97
CKD controls. Data are presented for three age cohorts (2–6, 7–12,
and 13–17 years) as age- and sex-dependent z-scores. Error bars
represent 95% confidence intervals. Dotted lines are for illustrative
purposes only, representing changes in patterns between the three
observed parameters

Pediatric Nephrology
1 3
z-score at ages 7–12years and an increase in APC-trans-
verse chest ratio z-scores from youngest to oldest patients
(p < 0.05) (Fig.2).
Biochemical predictors ofchest configuration
In patients with INC, standardized APC-height ratio
exhibited significant associations with clinical parameters
only before adolescence (ages 2–12years, Table3). Fac-
tors related to tubular dysfunction were associated with
APC-height ratio z-scores: lower sodium (ages 2–6years;
p < 0.05), lower phosphate (ages 2–6years and 7–12years)
and higher PTH (ages 7–12years) were significantly associ-
ated with more intense increase in APC-height ratio z-score
(each p < 0.05). Lower bicarbonate levels were associ-
ated with higher standardized APC-height ratio at ages
7–12years (p < 0.05).
Within early childhood (ages 2–6years), lower eGFR
values were generally significantly associated with a higher
APC-height ratio z-score (p < 0.01, Table3). Further, it
was found that, within the youngest age group (2–6years),
patients exhibited significantly less-progressive thoracic
deformation with age when eGFR values were higher
than the estimated marginal mean (90.7mL/min/1.73 m2)
of the respective group (β-value − 0.004 (95% CI –0.006
to − 0.002), p < 0.01).
As opposed to the limited early age range during which
significant associations were present for standardized APC-
height ratio, all INC age groups showed significant associa-
tions with assessed clinical parameters for APC-transverse
ratio z-score (Table4). In the youngest INC group, attrib-
utes of Fanconi syndrome (lower levels of sodium and
phosphate) exhibited significant associations with APC-
transverse chest ratio z-score elevation (each p < 0.01).
In the two older groups, however, lower eGFR (ages 7–12
and 13–17years; each p < 0.05) and lower serum bicarbo-
nate levels (ages 7–12years; p < 0.05) were associated with
higher standardized APC-transverse chest ratio.
Additional significant associations within the assessed
cluster of variables were visible, with lower hemoglobin
values at 7–12years, higher potassium levels at 2–6years
and higher calcium levels at 13–17years (each p < 0.05)
all being associated with standardized APC-transverse
chest ratio.
Table 3 Linear mixed-effects models of clinical determinants of chest proportions, i.e. anterior–posterior chest diameter/height ratio
(APC-height ratio), in three separate age groups of children with infantile nephropathic cystinosis and CKD controls
Data are presented as β-values (95% confidence intervals)
N describes the number of measurements per age subgroup; patients were examined multiple times within age groups; For estimations of effects
of calcium and phosphate, z-scores were used
Algebraic sign in β-values expresses positive ( +) or negative (–) association e.g. “-0.17” for sodium in the 2–6year old INC group represents
lower sodium levels to be associated with higher APC-height ratio
a p < 0.05; b p < 0.01
INC group CKD group
Parameter 2–6years
N = 32
7–12years
N = 29
13–17years
N = 31
2–6years
N = 77
7–12years
N = 100
13–17years
N = 44
Intercept 23.42 (6.61 to
40.24)b8.53 (− 10.36 to
27.41)
0.49 (− 17.38 to
18.35)
− 10.83 (− 34.96 to
13.30)
8.50 (− 4.37 to
21.36)
− 2.29 (− 35.97 to
31.38)
Hemoglobin 0.17 (− 0.30 to
0.63)
0.33 (− 0.08 to
0.74)
− 0.08 (− 0.33 to
0.17)
− 0.38 (− 0.73
to − 0.03)a − 0.03 (− 0.20 to
0.13)
0.16 (− 0.19 to 0.52)
HCO30.05 (− 0.13 to
0.24)
− 0.29 (− 0.50
to − 0.08)a0.11 (− 0.13 to
0.35)
− 0.15 (− 0.41 to
0.10)
− 0.10 (− 0.19 to
0.00)
− 0.08 (− 0.29 to
0.13)
Sodium − 0.17 (− 0.30
to − 0.04)a − 0.04 (− 0.17 to
0.09)
− 0.02 (− 0.14 to
0.10)
0.12 (− 0.06 to
0.29)
− 0.04 (− 0.13 to
0.06)
− 0.02 (− 0.25 to
0.21)
Potassium 0.10 (− 0.65 to
0.85)
0.57 (− 0.53 to
1.68)
0.39 (− 0.67 to
1.45)
0.74 (− 0.20 to
1.67)
− 0.07 (− 0.49 to
0.35)
1.06 (− 0.00 to 2.11)
Calcium − 0.16 (− 0.67 to
0.35)
0.43 (− 0.24 to
1.11)
0.21 (− 0.21 to
0.64)
0.30 (− 0.14 to
0.73)
− 0.12 (− 0.29 to
0.06)
0.22 (− 0.31 to 0.76)
Phosphate − 0.37 (− 0.73
to − 0.02)a − 0.63 (− 1.06
to − 0.20)b0.21 (− 0.03 to
0.46)
− 0.08 (− 0.59 to
0.44)
− 0.03 (− 0.23 to
0.16)
0.26 (− 0.10 to 0.63)
PTH (*100) 0.49 (− 0.21 to
1.19)
0.47 (0.05 to 0.89)a0.09 (− 0.27 to
0.44)
− 0.13 (− 1.12 to
0.85)
0.15 (− 0.26 to
0.56)
− 0.02 (− 0.62 to
0.57)
eGFR (*100) − 2.71 (− 4.45
to − 0.97)b − 1.89 (− 4.73 to
0.94)
0.97 (− 1.39 to
3.34)
− 0.45 (− 2.58 to
1.68)
0.20 (− 0.89 to
1.28)
0.73 (− 2.81 to 4.27)

Pediatric Nephrology
1 3
In contrast, only a few significant associations between
measures of chest proportions and clinical parameters were
noted in CKD controls. APC-height ratio z-score was associ-
ated with blood hemoglobin (ages 2–6years), while APC-
transverse chest ratio z-score was associated with serum
calcium (ages 7–12years) and serum phosphate (ages
13–17years, each p < 0.05; Tables3 and 4).
Discussion
This study revealed marked alterations in chest configuration
in children with INC characterized by increased chest depth
that is distinct from age-matched children with CKD stem-
ming from other causes. This underlines the multisystem
implications of the systemic lysosomal storage disease, espe-
cially pulmonary insufficiency that was previously reported
in 69% of adult patients with INC [29]. Adult restrictive lung
disease of extraparenchymal origin with reports of conical
chest shape [7, 9] is now shown to be preceded by increased
chest depth from childhood onward, which may even con-
tribute to the later clinical presentation, especially as such
a chest shape has previously been shown to be associated
with poorer prognosis in children facing respiratory stress,
i.e., infection [30].
Patients with cystinosis presented with substantially
reduced shoulder and chest width, as well as height, but
increased chest depth, resulting in a marked increase in
APC-height and APC-transverse chest ratio, in z-scores (> 1)
and in comparison to their peers with CKD. During early
childhood, standardized APC-height ratio appeared as the
most pronounced measure of chest disproportion in patients
with INC, reaching its maximum at 7–12years, and was
less pronounced in adolescent age likely due to the observed
parallel increase in height attributed to increased leg growth
[10]. Standardized APC-transverse ratio, on the other hand,
exhibited a sustained continuous increase, suggesting dis-
proportion within the horizontal plane of the ribcage of
INC patients to intensify with increasing age. This stresses
the importance of observing different ratios as indicators
of thoracic disproportion at different stages of childhood
development.
Accordingly, in the multivariate analysis, APC-height
ratio z-score exhibited significant associations with clinical
Table 4 Linear mixed-effects models of clinical determinants of chest proportion, i.e., anterior–posterior chest diameter/transverse chest
diameter ratio (APC-transverse ratio), in three separate age groups of children with infantile nephropathic cystinosis and CKD controls
Data are presented as β-values (95% confidence intervals)
N describes the number of measurements per age subgroup; patients were examined multiple times within age groups; for estimations of effects
of calcium and phosphate, z-scores were used. Algebraic sign in β-values expresses positive ( +) or negative (–) association, e.g., “ − 0.17” for
sodium in the 2–6-year-old INC group represents lower sodium levels to be associated with higher APC-height ratio
a p < 0.05
b p < 0.01
INC group CKD group
Parameter 2–6years
N = 32
7–12years
N = 29
13–17years
N = 31
2–6years
N = 77
7–12years
N = 100
13–17years
N = 44
Intercept 15.71 (2.94 to
28.48)
13.90 (− 7.43 to
35.22)
4.13 (− 20.22 to
28.47)
− 1.34 (− 23.84 to
21.16)
− 2.01 (− 17.71 to
13.69)
− 22.19 (− 52.38 to
8.00)
Hemoglobin 0.13 (− 0.22 to
0.48)
0.28 (− 0.18 to
0.74)
− 0.37 (− 0.71
to − 0.03)a − 0.29 (− 0.62 to
0.03)
0.00 (− 0.19 to
0.20)
0.32 (− 0.00 to 0.64)
HCO3 − 0.06 (− 0.20 to
0.08)
− 0.32 (− 0.55
to − 0.08)a0.19 (− 0.14 to
0.52)
− 0.07 (− 0.30 to
0.17)
− 0.04 (− 0.15 to
0.08)
− 0.11 (− 0.29 to
0.08)
Sodium − 0.15
(− 0.25 − 0.05)b − 0.03 (− 0.18
to − 0.12)
0.04 (− 0.12 to
0.21)
0.01 (− 0.15 to
0.18)
0.02 (− 0.01 to
0.14)
0.14 (− 0.06 to 0.34)
Potassium 1.38 (0.81 to 1.94)b − 0.99 (− 2.24 to
0.25)
− 1.39 (− 2.83 to
0.06)
0.68 (− 0.18 to
1.55)
− 0.03 (− 0.54 to
0.49)
0.32 (− 0.63 to 1.27)
Calcium 0.09 (− 0.30 to
0.48)
− 0.29 (− 1.05 to
0.47)
0.66 (0.08 to 1.23)a0.18 (− 0.23 to
0.58)
− 0.24 (− 0.46
to − 0.03)a0.10 (− 0.38 to 0.58)
Phosphate − 0.53 (− 0.69
to − 0.16)b − 0.37 (− 0.85 to
0.11)
− 0.05 (− 0.38 to
0.29)
0.01 (− 0.47 to
0.49)
0.03 (− 0.21 to
0.26)
0.42 (0.09 to 0.74)a
PTH (*100) 0.51 (− 0.02 to
1.04)
0.15 (− 0.32 to
0.62)
− 0.36 (− 0.85 to
0.13)
− 0.11 (− 1.03 to
0.82)
0.07 (− 0.43 to
0.57)
− 0.22 (− 0.75 to
0.31)
eGFR (*100) 0.00 (− 0.13 to
0.13)
− 3.28 (− 6.49
to − 0.08)a − 3.70 (− 6.92
to − 0.47)a1.60 (− 0.38 to
3.59)
0.06 (− 1.26 to
1.38)
0.78 (− 2.39 to 3.96)

Pediatric Nephrology
1 3
parameters only at pre-adolescent ages (6–12years), fur-
ther underlining the plasticity in that ratio during early
childhood. Its elevation was associated with the degree
of Fanconi syndrome (e.g., hypophosphatemia, low bicar-
bonate levels). Both hypophosphatemia and acidosis are
main causes of rickets resulting in impaired apoptosis of
hypertrophic chondrocytes and consecutive widening of the
growth plates in long bones and costal arches, and in severe
cases of for example nutritional rickets, resulting in pectus
carinatum, and thus increased chest depth [31, 32]. Despite
those implications of Fanconi syndrome for ribcage develop-
ment, our results suggest further factors to be at play. It is
generally assumed that Fanconi syndrome is the first clini-
cally apparent sign of INC, preceding the decline of eGFR.
However, present results show that, despite a relatively pre-
served eGFR at a young age (2–6years) [10], lower eGFR
values in early childhood are significantly associated with
increased APC-height ratio z-scores and thus the degree of
chest disproportion [1, 2]. Furthermore, the observed pro-
gressive increase with age in APC-height ratio z-scores
within the youngest age group was significantly less intense
when patients exhibited eGFR values above estimated mar-
ginal mean. This highlights the importance of early diag-
nosis and commencement of cysteamine therapy in these
patients, which has been shown to allow for the physiologi-
cally expected increase in eGFR during infancy and to ame-
liorate progressive CKD at a later age [33]. Whether a direct
causal link of reduced glomerular function and Fanconi syn-
drome with the observed thoracic deformation is present or
whether they are merely indicators of disease progression
or intensity remains unclear. In addition to the influences
of Fanconi syndrome and CKD–MBD (mineral and bone
disorder), cystinosis metabolic bone disease (CMBD) is
multifactorial and not yet fully understood. Influences of
this specific disease entity on the bones, e.g. the bones of the
ribcage, include effects of the CTNS mutation on the func-
tionality of osteoblasts and osteoclasts, as well as cysteamine
toxicity [6, 34–36].
Other factors than the evaluated parameters could con-
tribute to this either directly, e.g., vacuolar myopathy, which
has been reported to be associated with intensity of pulmo-
nary dysfunction in INC [7], or on a grander developmental
scale. A rather rounded thoracic shape is typically seen in
the early infantile period of healthy children [37], chang-
ing to a more ovoid shape during the first two years of life,
hence leading to a decreasing APC-transverse chest ratio
with age [37]. In INC patients, however, elevated thoracic
ratio z-scores continue to persist into childhood, suggesting
an aberrant thoracic development in the preceding infantile
period. Further, hypophosphatemic rickets is speculated to
delay ambulation [38–41], which is generally assumed to
normally contribute to changes in thoracic geometry and rib
orientation through postural changes [37, 42]. Alterations
in the growth hormone (GH)–insulin-like growth factor 1
(IGF1) axis and IGF1/GH downstream signaling through
malnutrition, insulin, and thyroid hormone deficiency in
INC [1, 43–45] might further hinder skeletal muscle growth
[46] and bone development [47], as well as the transition
between infantile and childhood developmental phases,
which is the main timeframe for changes in ribcage geom-
etry [37, 48, 49].
APC-transverse chest ratio z-scores were significantly
associated with several clinical parameters across all
age groups, which is in accordance with its continuous
increase across all observed ages. In the youngest group
(2–6years), those were predominantly related to Fanconi
syndrome (low serum sodium and phosphate concentra-
tions). Then, a gradual shift occurred, toward complica-
tions of INC usually occurring at higher ages, with APC-
transverse chest ratio z-score being associated with lower
eGFR values from 7–12years onward and lower hemo-
globin values at ages 13–17years. This age-related shift in
determinants seems to develop in parallel to INC disease
progression, as predominant tubular dysfunction is the
initial hallmark of INC, and loss of glomerular function
progresses over time [1, 43]. Surprisingly, a significant
negative association between standardized APC-transverse
chest ratio and serum potassium levels was seen in the
youngest INC group, which may be due to more intense
potassium substitution in severe cases of Fanconi syn-
drome. Further, higher calcium levels were unexpectedly
associated with higher APC-transverse chest ratio z-scores
in the oldest INC patients. As albumin-corrected calcium
was used for calculations and hypocalcemia and proteinu-
ria [39] might introduce discordance between calcium and
albumin levels [50, 51], interpretation of this particular
association is highly complex and exceeds the scope of
this analysis.
In contrast to patients with INC, chest configura-
tion in CKD controls was only mildly affected (values
within ± 1.0 z-score). The low biacromial diameter that
was visible across all ages in CKD controls and even
more pronounced in patients with INC is known to be
linked to low physical activity and poorer living condi-
tions [12, 13] and is thus likely due to the influences of
chronic disease. In the youngest age group in particular,
patients with CKD showed a strikingly different chest
shape pattern compared to patients with INC, where
chest depth was not significantly increased, but reduced,
and chest width was the best-preserved parameter. At
ages 13–17years, however, APC-transverse chest ratio
z-score significantly increased in CKD controls, cul-
minating in a pattern where chest depth was the high-
est individual parameter, similar to the pattern seen in
patients with INC, if far less intense and later in life, pos-
sibly as a result of longstanding complications (Fig.1).

Pediatric Nephrology
1 3
Low calcium and higher phosphate were associated with
higher APC-transverse chest ratio z-scores at ages 7–12
and 13–17years, respectively, possibly hinting at rachitic
thoracic deformation [14] due to CKD–MBD caused by
progressive CKD [52].
Our findings pose questions regarding possible clinical
implications of the observed chest shape [7, 9, 29] and
highlight the importance of the improvement of child-
hood development through optimal and early causal treat-
ment with cysteamine. Thus, further research would be
beneficial, regarding possible myopathy of the chest wall,
assessments of lung function and analyses of the pos-
sible impact of cysteamine therapy, e.g., time-averaged
weight-related cysteamine dosages or leukocyte cystine
levels, on chest configuration. Further, non-invasive posi-
tive pressure ventilation has been reported to alleviate
symptoms of restrictive respiratory dysfunction in adult
patients with INC [8, 9]. As an increase in chest depth
has previously been described to be linked to worse out-
comes in respiratory infection [30], and as such has been
found to be the leading cause of respiratory mortality in
patients with INC [29], earlier consideration of this treat-
ment option, as well as treatment for Fanconi syndrome,
may be beneficial for affected patients and needs to be
further evaluated. An early evaluation of patients with
INC regarding respiratory function may also be useful.
Those factors, however, exceed the scope of this pre-
sent analysis, which provided the initial description of
an INC-specific thoracic disproportion with increased
chest depth, which persists into adulthood, and is associ-
ated with the degree of tubular dysfunction and CKD.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00467- 023- 06058-x.
Acknowledgements The authors sincerely thank the patients, parents,
doctors, and nurses from the participating centers and especially Sabine
Wiedenhöft for her great contribution through organizing and coordi-
nating this multicenter study.
Author contribution MŽ, SM, and DH designed the study. MŽ per-
formed anthropometric measurements. KH, AB, MJK, JO, HB, JT,
LTW, BAR, KA, BT, MH, KF, and DH were involved in recruiting
patients and providing clinical data in each specific center. SM, RK,
CJ, and MŽ collected clinical data, and MŽ, SM, and LP performed the
statistical analysis and interpreted the data. SM, RK, CJ, MB, and MŽ
wrote the first draft of the manuscript. MŽ and DH revised the manu-
script. All authors reviewed the manuscript critically and approved the
final version for publication.
Funding Open Access funding enabled and organized by Projekt
DEAL. This work was supported by a research grant from Horizon,
USA, to Dieter Haffner.
Data availability The data that support the findings of this study are
available on request from the corresponding author. The data are not
publicly available due to privacy or ethical restrictions.
Declarations
Ethics approval The study received appropriate Ethics Committee
approval from the Institutional Review Board at each site and was
performed in accordance with the Declaration of Helsinki.
Consent to participate Written informed consent was obtained from all
parents/guardians, with consent or assent from patients when appropri-
ate for their age.
Conflict of interest Dieter Haffner received speaker fees and research
grants from Horizon and Chiesi. Jun Oh received speaker fees from
Horizon and Chiesi. Burkhard Tönshoff participated in advisory
boards for Chiesi. Julia Thumfart received speaker fees from Horizon.
Lutz T. Weber received speaker fees from Chiesi. KH was supported
by the Cystinosis Foundation Germany.
All other authors declare that they have no conflict of interest.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article's Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.
References
1. Nesterova G, Gahl WA (2013) Cystinosis: The evolution of a treat-
able disease. Pediatr Nephrol 28:51–59. https:// doi. org/ 10. 1007/
s00467- 012- 2242-5
2. Cherqui S, Courtoy PJ (2017) The renal Fanconi syndrome in cys-
tinosis: pathogenic insights and therapeutic perspectives. Nat Rev
Nephrol 13:115–131. https:// doi. org/ 10. 1038/ nrneph. 2016. 182
3. Veys KR, Elmonem MA, Arcolino FO, van den Heuvel L, Levtch-
enko E (2017) Nephropathic cystinosis: an update. Curr Opin
Pediatr 29:168–178. https:// doi. org/ 10. 1097/ MOP. 00000 00000
000462
4. Gahl WA, Dalakas MC, Charnas L, Chen KT, Pezeshkpour GH,
Kuwabara T, Davis SL, Chesney RW, Fink J, Hutchison HT
(1988) Myopathy and cystine storage in muscles in a patient with
nephropathic cystinosis. N Engl J Med 319:1461–1464. https://
doi. org/ 10. 1056/ NEJM1 98812 01319 2206
5. Charnas LR, Luciano CA, Dalakas M, Gilliatt RW, Bernardini
I, Ishak K, Cwik VA, Fraker D, Brushart TA, Gahl WA (1994)
Distal vacuolar myopathy in nephropathic cystinosis. Ann Neurol
35:181–188. https:// doi. org/ 10. 1002/ ana. 41035 0209
6. Haffner D, Leifheit-Nestler M, Alioli C, Bacchetta J (2022) Mus-
cle and bone impairment in infantile nephropathic cystinosis: New
concepts. Cells 11:170. https:// doi. org/ 10. 3390/ cells 11010 170
7. Anikster Y, Lacbawan F, Brantly M, Gochuico BL, Avila NA,
Travis W, Gahl WA (2001) Pulmonary dysfunction in adults with
nephropathic cystinosis. Chest 119:394–401. https:// doi. org/ 10.
1378/ chest. 119.2. 394
8. El-Naggari MA, Elnour I, Al-Kindy H, Al-Shahrabally A, Abdel-
mogheth AA (2014) Successful management of a neglected case
of nephropathic cystinosis. Sultan Qaboos Univ Med J 14:245

Pediatric Nephrology
1 3
9. Edens MA, van Son WJ, de Greef MHG, Levtchenko EN, Blijham T,
Wijkstra PJ (2006) Successful treatment of respiratory dysfunction
in cystinosis by nocturnal non-invasive positive pressure ventilation.
Clin Nephrol 66:306–309. https:// doi. org/ 10. 5414/ cnp66 306
10. Kluck R, Müller S, Jagodzinski C, Hohenfellner K, Büscher A,
Kemper MJ, Oh J, Billing H, Thumfart J, Weber LT, Acham-
Roschitz B, Arbeiter K, Tönshoff B, Hagenberg M, Kanzelmeyer
N, Pavičić L, Haffner D, Zivicnjak M (2022) Body growth, upper
arm fat area, and clinical parameters in children with nephropathic
cystinosis compared with other pediatric chronic kidney disease
entities. J Inherit Metab Dis 45:192–202. https:// doi. org/ 10. 1002/
jimd. 12473
11. Van Stralen KJ, Emma F, Jager KJ, Verrina E, Schaefer F, Laube
GF, Lewis MA, Levtchenko EN (2011) Improvement in the renal
prognosis in nephropathic cystinosis. Clin J Am Soc Nephrol
6:2485–2491. https:// doi. org/ 10. 2215/ CJN. 02000 311
12. Mesa MS, Fuster V, Sánchez-Andrés A, Marrodán D (1993)
Secular changes in stature and biacromial and bicristal diam-
eters of young adult Spanish males. Am J Hum Biol 5:705–709.
https:// doi. org/ 10. 1002/ ajhb. 13100 50613
13. Cacciari E, Mazzanti L, Tassinari D, Bergamaschi R, Magnani
C, Ghini T, Tani G, Drago E, Nanni G, Cobianchi C (1989)
Growth and sport. J Endocrinol Invest 12:53–57
14. Lips P, de Jongh RT (2018) Vitamin D deficiency in immigrants.
Bone Rep 9:37–41. https:// doi. org/ 10. 1016/j. bonr. 2018. 06. 001
15. Ewert A, Leifheit-Nestler M, Hohenfellner K, Büscher A,
Kemper MJ, Oh J, Billing H, Thumfart J, Stangl G, Baur AC,
Föller M, Feger M, Weber LT, Acham-Roschitz B, Arbeiter K,
Tönshoff B, Zivicnjak M, Haffner D (2020) Bone and mineral
metabolism in children with nephropathic cystinosis compared
with other CKD entities. J Clin Endocrinol Metab 105:dgaa267.
https:// doi. org/ 10. 1210/ clinem/ dgaa2 67
16. Zivicnjak M, Franke D, Filler G, Haffner D, Froede K, Nissel
R, Haase S, Offner G, Ehrich JHH, Querfeld U (2006) Growth
impairment shows an age-dependent pattern in boys with
chronic kidney disease. Pediatr Nephrol 22:420–429. https://
doi. org/ 10. 1007/ s00467- 006- 0345-6
17. Zivicnjak M, Narancić NS, Szirovicza L, Franke D, Hrenović
J, Bisof V (2003) Gender-specific growth patterns for stature,
sitting height and limbs length in Croatian children and youth
(3 to 18 years of age). Coll Antropol 27:321–334
18. Zivicnjak M, Smolej Narancić N, Szirovicza L, Franke D,
Hrenović J, Bisof V, Tomas Z, Skarić-Jurić T (2008) Gender-
specific growth patterns of transversal body dimensions in Croa-
tian children and youth (2 to 18 years of age). Coll Antropol
32:419–431
19. Payne RB, Little AJ, Williams RB, Milner JR (1973) Interpreta-
tion of serum calcium in patients with abnormal serum proteins.
Br Med J 4:643–646
20. De Souza VC, Rabilloud M, Cochat P, Selistre L, Hadj-Aissa
A, Kassai B, Ranchin B, Berg U, Herthelius M, Dubourg L
(2012) Schwartz formula: is one k-coefficient adequate for all
children? PLoS One 7:e53439. https:// doi. org/ 10. 1371/ journ al.
pone. 00534 39
21. Spackman DH, Stein WH, Moore S (1958) Automatic recording
apparatus for use in chromatography of amino acids. Anal Chem
30:1190–1206. https:// doi. org/ 10. 1021/ ac601 39a006
22. Linden S, Klank S, Harms E, Grüneberg M, Park JH, Marquardt
T (2020) Cystinosis: therapy adherence and metabolic monitor-
ing in patients treated with immediate-release cysteamine. Mol
Genet Metab Rep 24:100620. https:// doi. org/ 10. 1016/j. ymgmr.
2020. 100620
23. Adeli K, Higgins V, Nieuwesteeg M, Raizman JE, Chen Y,
Wong SL, Blais D (2015) Biochemical marker reference val-
ues across pediatric, adult, and geriatric ages: establishment of
robust pediatric and adult reference intervals on the basis of the
Canadian health measures survey. Clin Chem 61:1049–1062.
https:// doi. org/ 10. 1373/ clinc hem. 2015. 240515
24. KDIGO (2012) Clinical practice guideline for anemia in chronic
kidney disease. Kidney Int Suppl 2:288–291
25. KDOQI (2009) Clinical practice guideline for nutrition in chil-
dren with CKD: 2008 update executive summary. Am J Kidney
Dis 53:11. https:// doi. org/ 10. 1053/j. ajkd. 2008. 11. 017
26. de Kieviet W, Slaats EH, Abeling NG (1986) Pediatric refer-
ence values for calcium, magnesium and inorganic phosphorus
in serum obtained from Bhattacharya plots for data from unse-
lected patients. J Clin Chem Clin Biochem 24:233–242. https://
doi. org/ 10. 1515/ cclm. 1986. 24.4. 233
27. Voigt M, Schneider KT, Jährig K (1996) Analysis of a 1992
birth sample in Germany. 1: New percentile values of the body
weight of newborn infants. Geburtshilfe Frauenheilkd 56:550–
558. https:// doi. org/ 10. 1055/s- 2007- 10232 83
28. Lane PH (2005) Puberty and chronic kidney disease. Adv Chronic
Kidney Dis 12:372–377. https:// doi. org/ 10. 1053/j. ackd. 2005. 07.
009
29. Gahl WA, Balog JZ, Kleta R (2007) Nephropathic cystinosis in
adults: Natural history and effects of oral cysteamine therapy. Ann
Intern Med 147:242–250. https:// doi. org/ 10. 7326/ 0003- 4819- 147-
4- 20070 8210- 00006
30. Pascoal LM, de Oliveira Lopes MV, da Silva VM, Beltrão BA,
Chaves DBR, Nunes MM, de Castro NB (2016) Prognostic clini-
cal indicators of short-term survival for ineffective breathing
pattern in children with acute respiratory infection. J Clin Nurs
25:752–759. https:// doi. org/ 10. 1111/ jocn. 13064
31. Haffner D, Leifheit-Nestler M, Grund A, Schnabel D (2021) Rick-
ets guidance: part I-diagnostic workup. Pediatr Nephrol 37:2013–
2036. https:// doi. org/ 10. 1007/ s00467- 021- 05328-w
32. Aung H, Soe K, Smithuis FF, Lamb T, Aung MW, Smithuis FM
(2021) Case report: children with severe nutritional rickets in the
naga region in northwest myanmar, on the border with india. Am
J Trop Med Hyg 105:217–221. https:// doi. org/ 10. 4269/ ajtmh.
20- 1431
33. Markello TC, Bernardini IM, Gahl WA (1993) Improved renal
function in children with cystinosis treated with cysteamine. N
Engl J Med 328:1157–1162. https:// doi. org/ 10. 1056/ NEJM1
99304 22328 1604
34. Langman CB (2017) Bone complications of cystinosis. J Pediatr
183:S2–S4. https:// doi. org/ 10. 1016/j. jpeds. 2016. 12. 052
35. Battafarano G, Rossi M, Rega LR, Di Giovamberardino G, Pastore
A, D’Agostini M, Porzio O, Nevo N, Emma F, Taranta A, Del
Fattore A (2019) Intrinsic bone defects in cystinotic mice. Am J
Pathol 189:1053–1064. https:// doi. org/ 10. 1016/j. ajpath. 2019. 01.
015
36. Machuca-Gayet I, Quinaux T, Bertholet-Thomas A, Gaillard
S, Claramunt-Taberner D, Acquaviva-Bourdain C, Bacchetta J
(2020) Bone disease in nephropathic cystinosis: beyond renal
osteodystrophy. Int J Mol Sci 21:3109. https:// doi. org/ 10. 3390/
ijms2 10931 09
37. Openshaw P, Edwards S, Helms P (1984) Changes in rib cage
geometry during childhood. Thorax 39:624–627. https:// doi. org/
10. 1136/ thx. 39.8. 624
38. Hohenfellner K, Rauch F, Ariceta G, Awan A, Bacchetta J, Berg-
mann C, Bechtold S, Cassidy N, Deschenes G, Elenberg E, Gahl
WA, Greil O, Harms E, Herzig N, Hoppe B, Koeppl C, Lewis
MA, Levtchenko E, Nesterova G, Santos F, Schlingmann KP,
Servais A, Soliman NA, Steidle G, Sweeney C, Treikauskas U,
Topaloglu R, Tsygin A, Veys K, Vigier V, R, Zustin J, Haffner D,
(2019) Management of bone disease in cystinosis: statement from
an international conference. J Inherit Metab Dis 42:1019–1029.
https:// doi. org/ 10. 1002/ jimd. 12134

Pediatric Nephrology
1 3
39. Agarwal A, Gulati D, Rath S, Walia M (2009) Rickets: a cause of
delayed walking in toddlers. Indian J Pediatr 76:269–272. https://
doi. org/ 10. 1007/ s12098- 009- 0052-y
40. Sahni SS, Kakkar S, Kumar R, Goraya JS (2021) Osteomalacic myo-
pathy in children and adolescents with vitamin-D deficiency. Neurol
India 69:1650–1654. https:// doi. org/ 10. 4103/ 0028- 3886. 333492
41. Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L,
Guillaume-Czitrom S, Kamenicky P, Nevoux J, Prié D, Rothen-
buhler A, Wicart P, Harvengt P (2014) Therapeutic management
of hypophosphatemic rickets from infancy to adulthood. Endocr
Connect 3:13. https:// doi. org/ 10. 1530/ EC- 13- 0103
42. Hershenson MB, Colin AA, Wohl ME, Stark AR (1990) Changes
in the contribution of the rib cage to tidal breathing during
infancy. Am Rev Respir Dis 141:922–925. https:// doi. org/ 10.
1164/ ajrccm/ 141.4_ Pt_1. 922
43. Gahl WA, Thoene JG, Schneider JA (2002) Cystinosis. N Engl J
Med 347:111–121. https:// doi. org/ 10. 1056/ NEJMr a0205 52
44. Gultekingil Keser A, Topaloglu R, Bilginer Y, Besbas N (2014)
Long-term endocrinologic complications of cystinosis. Minerva
Pediatr 66:123–130
45. Kasimer RN, Langman CB (2021) Adult complications of nephro-
pathic cystinosis: a systematic review. Pediatr Nephrol 36:223–
236. https:// doi. org/ 10. 1007/ s00467- 020- 04487-6
46. Schiaffino S, Mammucari C (2011) Regulation of skeletal
muscle growth by the IGF1-akt/PKB pathway: Insights from
genetic models. Skelet Muscle 1:4. https:// doi. org/ 10. 1186/
2044- 5040-1-4
47. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Sloot-
weg MC (1998) Growth hormone and bone. Endocr Rev 19:55–
79. https:// doi. org/ 10. 1210/ edrv. 19.1. 0324
48. Low LC, Tam SY, Kwan EY, Tsang AM, Karlberg J (2001)
Onset of significant GH dependence of serum IGF-I and
IGF-binding protein 3 concentrations in early life. Pediatr
Res 50:737–742. https:// doi. org/ 10. 1203/ 00006 450- 20011
2000- 00018
49. Hochberg Z (2009) Evo-devo of child growth II: human life his-
tory and transition between its phases. Eur J Endocrinol 160:135–
141. https:// doi. org/ 10. 1530/ EJE- 08- 0445
50. Ong GSY, Walsh JP, Stuckey BGA, Brown SJ, Rossi E, Ng
JL, Nguyen HH, Kent GN, Lim EM (2012) The importance
of measuring ionized calcium in characterizing calcium
status and diagnosing primary hyperparathyroidism. J Clin
Endocrinol Metab 97:3138–3145. https:// doi. org/ 10. 1210/ jc.
2012- 1429
51. Minisola S, Pepe J, Cipriani C (2021) Measuring serum calcium:
total, albumin-adjusted or ionized? Clin Endocrinol (Oxf) 95:267–
268. https:// doi. org/ 10. 1111/ cen. 14362
52. Santos F, Díaz-Anadón L, Ordóñez FA, Haffner D (2021) Bone
disease in CKD in children. Calcif Tissue Int 108:423–438.
https:// doi. org/ 10. 1007/ s00223- 020- 00787-z
Publisher's note Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Authors and Aliations
SophiaMüller1· RikaKluck1· CelinaJagodzinski1· MalinaBrügelmann1· KatharinaHohenfellner2·
AnjaBüscher3· MarkusJ.Kemper4· KerstinFröde1· JunOh5· HeikoBilling6· JuliaThumfart7· LutzT.Weber8·
BirgitAcham‑Roschitz9· KlausArbeiter10· BurkhardTönsho11· MartinaHagenberg12· LeoPavičić13·
DieterHaner1· MiroslavZivicnjak1
* Miroslav Zivicnjak
zivicnjak.miroslav@mh-hannover.de
1 Department ofPediatric Kidney, Liver andMetabolic
Diseases, Hannover Medical School, Children’s Hospital,
Carl-Neuberg-Str. 1, 30625Hannover, Germany
2 Division ofPediatric Nephrology, Children’s Hospital,
Rosenheim, Germany
3 Department ofPediatrics II, University Hospital Essen,
Essen, Germany
4 Asklepios Hospital, Hamburg, Germany
5 Division ofPediatric Nephrology, University Children’s
Hospital Hamburg, Hamburg, Germany
6 Clinic forPediatric andAdolescent Medicine, RHK Clinic
Ludwigsburg, Ludwigsburg, Germany
7 Department ofPediatric Gastroenterology, Nephrology
andMetabolic Diseases, Charité-Universitätsmedizin Berlin,
Berlin, Germany
8 Pediatric Nephrology, Children’s andAdolescents’ Hospital,
University ofCologne, Faculty ofMedicine andUniversity
Hospital, Cologne, Germany
9 Department ofPediatrics, Medical University Graz, Graz,
Austria
10 Division ofPediatric Nephrology andGastroenterology,
Medical University Vienna, Vienna, Austria
11 Department ofPediatrics I, University Children’s Hospital
Heidelberg, Heidelberg, Germany
12 Children’s Hospital St. Elisabeth andSt. Barbara,
Halle(Saale), Germany
13 Zagreb, Croatia