Growth hormone treatment in the pre-transplant period is associated with superior outcome after pediatric kidney transplantation

Abstract

Background
Recombinant human growth hormone (rhGH) is frequently used for treatment of short stature in children with chronic kidney disease (CKD) prior to kidney transplantation (KT). To what extent this influences growth and transplant function after KT is yet unknown.

Methods
Post-transplant growth (height, sitting height, leg length) and clinical parameters of 146 CKD patients undergoing KT before the age of 8 years, from two German pediatric nephrology centers, were prospectively investigated with a mean follow-up of 5.56 years. Outcome in patients with (rhGH group) and without (non-prior rhGH group) prior rhGH treatment was assessed by the use of linear mixed-effects models.

Results
Patients in the rhGH group spent longer time on dialysis and less frequently underwent living related KT compared to the non-prior rhGH group but showed similar height z -scores at the time of KT. After KT, steroid exposure was lower and increments in anthropometric z -scores were significantly higher in the rhGH group compared to those in the non-prior rhGH group, although 18% of patients in the latter group were started on rhGH after KT. Non-prior rhGH treatment was associated with a faster decline in transplant function, lower hemoglobin, and higher C-reactive protein levels (CRP). After adjustment for these confounders, growth outcome did statistically differ for sitting height z -scores only.

Conclusions
Treatment with rhGH prior to KT was associated with superior growth outcome in prepubertal kidney transplant recipients, which was related to better transplant function, lower CRP, less anemia, lower steroid exposure, and earlier maturation after KT.

Graphical abstract
A higher resolution version of the Graphical abstract is available as Supplementary information

Full text

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Pediatric Nephrology
https://doi.org/10.1007/s00467-021-05222-5
ORIGINAL ARTICLE
Growth hormone treatment inthepre‑transplant period isassociated
withsuperior outcome afterpediatric kidney transplantation
CelinaJagodzinski1· SophiaMueller1· RikaKluck1· KerstinFroede1· LeoPavičić2· JuttaGellermann3·
DominikMueller3· UweQuerfeld3· DieterHaner1· MiroslavZivicnjak1
Received: 28 May 2021 / Revised: 6 July 2021 / Accepted: 6 July 2021
© The Author(s) 2021
Abstract
Background Recombinant human growth hormone (rhGH) is frequently used for treatment of short stature in children with
chronic kidney disease (CKD) prior to kidney transplantation (KT). To what extent this influences growth and transplant
function after KT is yet unknown.
Methods Post-transplant growth (height, sitting height, leg length) and clinical parameters of 146 CKD patients undergoing
KT before the age of 8years, from two German pediatric nephrology centers, were prospectively investigated with a mean
follow-up of 5.56years. Outcome in patients with (rhGH group) and without (non-prior rhGH group) prior rhGH treatment
was assessed by the use of linear mixed-effects models.
Results Patients in the rhGH group spent longer time on dialysis and less frequently underwent living related KT compared
to the non-prior rhGH group but showed similar height z-scores at the time of KT. After KT, steroid exposure was lower
and increments in anthropometric z-scores were significantly higher in the rhGH group compared to those in the non-prior
rhGH group, although 18% of patients in the latter group were started on rhGH after KT. Non-prior rhGH treatment was
associated with a faster decline in transplant function, lower hemoglobin, and higher C-reactive protein levels (CRP). After
adjustment for these confounders, growth outcome did statistically differ for sitting height z-scores only.
Conclusions Treatment with rhGH prior to KT was associated with superior growth outcome in prepubertal kidney trans-
plant recipients, which was related to better transplant function, lower CRP, less anemia, lower steroid exposure, and earlier
maturation after KT.
Keywords Children· Growth hormone· Kidney transplantation· Growth· Kidney function· Development
Introduction
Kidney transplantation (KT) is the therapy of choice in pedi-
atric patients with chronic kidney disease (CKD) stage 5 [1].
However, it only manages to correct the disturbances associated
with CKD to a certain extent. Indeed, disproportionate short
stature with preferential impairment of leg growth is a given in
children with CKD stage 5 and catch-up growth after KT is usu-
ally limited [2]. Recent studies still report reduced adult height
in patients with childhood-onset CKD stage 5 in about 40% of
patients despite successful KT [3]. Growth outcome after KT is
associated with many factors including patient age, transplant
function, steroid exposure, parental height, birth parameters,
and initial degree of growth retardation [3–8]. Careful control
of caloric intake, metabolic disturbances including acidosis, and
the CKD mineral and bone disorder (CKD–MBD), is of utmost
importance to achieve optimal height at the time of KT, which
is significantly associated with adult height [4, 9]. In addition,
treatment with recombinant human growth hormone (rhGH)
is a proven measure to improve growth in short children with
CKD stages 3–5D [10]. However, rhGH is currently under-
utilized in short children with CKD stage 5 in North America
and many European countries, which is partly due to family
* Miroslav Zivicnjak
zivicnjak.miroslav@mh-hannover.de
1 Department ofPediatric Kidney, Liver andMetabolic
Diseases, Children’s Hospital, Hannover Medical School,
Carl-Neuberg-Str. 1, 30625Hannover, Germany
2 Zagreb, Croatia
3 Department ofPediatrics, Division ofGastroenterology,
Nephrology andMetabolic Diseases, Charité
- Universitätsmedizin Berlin, Campus Virchow-Klinikum,
Augstenburger Platz 1, 13353Berlin, Germany

Pediatric Nephrology
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refusal, non-adherence, and lack of reimbursement by insurance
companies [11–14]. Its use after KT was also shown to be effec-
tive but concern has been raised that it may promote rejection
episodes and thereby impair long-term graft function [15]. At
present, discontinuation of rhGH therapy at the time of KT is
standard practice. The currently recommended strategy for opti-
mizing post-transplant growth consists of steroid-minimizing
immunosuppressive protocols and monitoring of spontaneous
growth after KT for at least 12months before considering rhGH
treatment [10, 16]. Whether treatment with rhGH prior to KT
has long-term effects on growth and clinical features after KT
has not been investigated. Therefore, we evaluated post-trans-
plant growth in 146 prepubertal kidney allograft recipients who
received rhGH treatment prior to KT or not.
Methods
Study design andpatients
From May 1998 until January 2020, a total of 947 children
who received KT were enrolled in the CKD Growth and
Development Study. This is a prospective observational cohort
study in two pediatric nephrology centers in Germany (Han-
nover Medical School and Charité Universitätsmedizin, Ber-
lin) assessing growth and clinical parameters of all available
CKD patients stages 3–5D and after KT in yearly intervals as
previously described [2]. The study was approved by the local
ethics committees, and research was performed in accordance
with the Declaration of Helsinki. Study participants and/or
their parents gave their consent prior to participation.
For this analysis, all first time graft recipients who under-
went KT before the age of 8years and with at least one valid
follow-up examination were included until the age of 18years.
Primary diseases included congenital anomalies of the kidney
and urinary tract (59%), glomerulopathies (25%), and others
(16%). Patients with syndromic diseases, e.g., Jeune syndrome
(n = 2), Schimke (n = 2), Prune-Belly syndrome (n = 1), Ari-
mas syndrome (n = 1), and Denys-Drash syndrome (n = 1), were
excluded. In addition, we excluded patients who had to resume
dialysis treatment after KT or who had to be re-transplanted
(n = 21), who underwent liver or hearttransplantations (n = 6),
or who had to be given rhGH before and after KT (n = 9). All
annual follow-up interval measurements from immediately after
KT (0.01–0.99years) up to a maximum of 10 (10.00–10.99)
years after KT were included. Thus, the data of 146 patients
(92 male), who underwent a total of 812 annual measurements,
with a mean follow-up of 5.56years could be analyzed.
Patients were divided in two groups: (i) patients who
received rhGH prior to KT (rhGH group, n = 52), and (ii)
patients who received no rhGH prior to KT (non-prior rhGH
group, n = 94). In 17 out of 94 patients (18%) of the latter
group, rhGH was started after KT, but in none of the former
group. Indications for the use of rhGH prior to KT were a
height SD score (SDS) < − 2.0 and a height velocity < 25th
percentile in patients with CKD stages 3–5D. The same aux-
ological parameters were used as indications for use of rhGH
post KT after a minimum follow-up of 12months [10].
Primary immunosuppressive protocols included daily
prednisolone treatment. By week 8, the prednisolone dos-
age was tapered down to 4mg/m2/day. All patients were
kept on daily prednisolone until 2007. From 2007 onwards,
patients were regularly weaned off steroids between six
and twelve months post KT in case of stable graft function
and lack of rejection. The prescribed dietary intake was in
accordance with targeted requirements. Dietary intake was
routinely monitored in all CKD and transplanted patients
every 3–12months, depending on patient’s age.
Genetic target height was calculated from mid-parental
height: mother’s height + father’s height / 2 ± 6.5cm in boys
and girls, respectively [17]. Data on gestational age were
obtained from the children’s health care booklets. The point
of attainment of CKD stage 5 was defined by estimated glo-
merular filtration rate (eGFR) below 15ml/min/1.73 m2, ini-
tiation of dialysis, or pre-emptive KT (no prior dialysis). The
revised Schwartz formula was used to calculate eGFR [18].
Newborns were classified as small for gestational age (SGA)
if birth weight or length was < 10th percentile using national
growth charts [19]. Anemia was defined using the World
Health Organization age- and sex-specific hemoglobin
thresholds for defining anemia in children [20]. There was
no significant difference in age distribution of both groups in
any year from directly after KT until end of follow-up. Bone
age delay was calculated as the difference between bone age
and chronological age as a measure of skeletal maturation.
Anthropometry
Anthropometric measurements included total body height,
sitting height, and leg length, as described [21]. The sit-
ting height index was calculated as the ratio between sit-
ting height and stature as a measure of body disproportion.
All measurements were performed by the same investigator
(M. Z.), as recommended by the International Biological
Program [22] with the use of standardized equipment (Dr.
Keller, I Stadiometer-Limbach-Oberfrohna, Germany; Siber
Hegner Anthropometer Zürich, Switzerland).
Statistical analyses
Data are given as mean ± SD and/or 95% confidence interval
(CI) unless indicated otherwise. SDS values for anthropo-
metric parameters were calculated according to the equation
SDS = (xi–xs) /SD (xi representing individual patient value, xs
as well as SD representing corresponding value from age- and

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sex-matched healthy reference peers) [23, 24]. The normal-
ity of distribution was evaluated by the Shapiro–Wilk test for
each cohort (time after KT) for each variable. Measurements
were grouped according to time after KT and age cohorts using
yearly intervals. Differences between groups were assessed by
unpaired t test or the Mann–Whitney U test, as appropriate.
Linear mixed-effects models (Mixed) and the Kronecker
product model were used to generate a time-dependent analy-
sis of anthropometric and clinical data including both time
after KT and age cohort as well as the factor treatment (rhGH
versus non-prior rhGH). The combination of unstructured
and autoregressive covariance matrix type (UN_AR1) turned
out to be the most appropriate for our analyses. In addition,
anthropometrical data were adjusted for covariates, i.e., age
at CKD stage 5, age at KT, average daily steroid dosage, time
after KT, average eGFR, pH, hemoglobin, and HCO3 values
during the preceding 12months. Clinical predicted determi-
nants of kidney function after KT in the two treatment groups
were adjusted for the following covariates: age at CKD stage
5, age at KT, average daily steroid dosage, time after KT, and
averages of hemoglobin, pH, and HCO3 during the preced-
ing year. The standard statistical package SPSS for Windows,
version 26.0 (IBM Corp), was used for statistical calculations.
Results were considered significant at a level of p < 0.05.
Results
Clinical characteristics of the study cohorts are presented
in Table1. Patient groups did not differ with respect to sex,
male–female incidence, age when CKD stage 5 was reached
and KT, time of follow-up, genetic target height, rates of
congenital CKD, pre-emptive KT, and SGA. However,
patients in the rhGH group less frequently underwent liv-
ing related KT (19% versus 34%) and spent longer time on
dialysis (median, 1.47years versus 0.78years) (Table1).
Growth hormone therapy was initiated in the rhGH group at a
median age of 1.93years, continued over a median period of
1.23years and was stopped in all patients at the time of KT.
By contrast, after KT, rhGH treatment was initiated in the
non-prior rhGH group (18%) only. The mean time interval
between KT and initiation of rhGH treatment in the patients
who received rhGH after KT was 5.71years. The rhGH group
less frequently received treatment with erythropoietin, and
less frequently showed anemia which was most pronounced
during late post-transplant years (p < 0.05) (Table1, Fig.1).
Post‑transplant growth andmaturation inpatients
withandwithoutprior rhGH treatment
Before KT, z-scores for anthropometric data did not dif-
fer significantly between groups and 61.3% and 67.9%,
respectively, of patients with and without prior rhGH treat-
ment presented with short stature (< − 2.0 SDS) (Fig.2).
After KT, a sustained and significant increase in mean
standardized height was noted in patients with prior rhGH
treatment (pre-KT, − 2.08 SDS; 4years post-KT, − 1.11;
p < 0.05), whereas in patients without prior rhGH treatment
the change of standardized height was significant only until
1year post-KT (Fig.2). Maximum discrepancy in stature
between groups occurred 7years after KT (− 0.85 SDS ver-
sus − 1.76 SDS, p < 0.05). Consequently, patients with prior
rhGH treatment were generally taller with respect to height,
sitting height (each p < 0.05), and leg length (p = 0.081,
Table2). This was mainly related to a more pronounced
increase in leg length in early post-transplant years in the
rhGH group, resulting in z-scores of − 0.97 in the rhGH
group and − 1.67 in the non-prior rhGH group 5years after
KT (p < 0.05, Fig.2).
Consequently, the frequency of short stature after KT was
lower in the rhGH group (35.7% versus 50.0%) which was
most pronounced 7years after KT (11.1% versus 45.2%,
p < 0.01). Likewise, reduced sitting height and leg length
(< − 2.0 SDS) were more frequently noted in the non-prior
rhGH group which was also most pronounced 7years after
KT (sitting height, 24.4% versus 0.0%; leg length, 48.8 ver-
sus 11.1%; each p < 0.05). By contrast, the mean standard-
ized sitting height index was comparably elevated in both
groups (Table2).
The typical prepubertal peak of growth in stature and leg
length occurred 5years after KT in the rhGH group, whereas
the non-prior rhGH group showed a delay in leg length
and total body height, peaking 6years after KT (Fig.2).
Instead, sitting height showed the same timing in growth
gain in both groups, peaking 5years after KT, but differ-
ing in growth intensity (rhGH group − 0.41 versus non-prior
rhGH group − 0.92 SDS).
Likewise, age at menarche occurred much later in the
non-prior rhGH group than in the rhGH group (13.02years
versus 11.79years, respectively, p < 0.05, Table1). Mean
bone age delay was comparable in both groups at last assess-
ment before KT (p = 0.497), but was significantly more
pronounced in the non-prior rhGH group after KT (rhGH
group − 0.71 years; non-prior rhGH group − 1.23 years,
p < 0.05, Table1, Fig.3).
Transplant function andbiochemical parameters
inpatients withandwithoutprior rhGH treatment
Mean eGFR values were significantly higher in the rhGH
group after KT overall (71.21ml/min/1.73 m2 versus
59.20ml/min/1.73 m2) (Table1). Mean eGFR peaked
1year and 2years post-KT and amounted to 75ml/
min/1.73 m2 and 80 ml/min/1.73 m2 in the non-prior
rhGH group and the rhGH group, respectively (Fig.4).

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Table. 1 Clinical characteristics of 146 pediatric kidney transplant recipients with or without rhGH treatment prior to transplantation
IQR interquartile range, KT kidney transplantation, Epo erythropoietin, SGA small for gestational age, rhGH recombinant human growth hor-
mone, SDS standard deviation score, eGFR estimated glomerular filtration rate, PTH parathyroid hormone, CRP C-reactive protein
AA Annual average: AVERAGE of measurements in the year prior to annual assessment
a Descriptive statistic (non-repeated measurements) are given as median and interquartile range (25th–75th percentile)
b Repeated measurement (estimated marginal means) during the observation period are based on actual measurement or annual average values
(AA), repeated measurements within the same individual (evaluated with the linear mixed model, random patients, and age cohorts)
rhGH prior to KT No rhGH prior to KT
Incidence No. of cases/
measurements Incidence No. of cases/
measurements p value
Male, % 61.5 32 of 52 63.8 60 of 94 0.460
Congenital CKD, % 78.8 41 of 52 77.7 73 of 94 0.522
Preemptive KT, % 34.6 18 of 52 33.0 31 of 94 0.491
Living donor, % 19.2 10 of 52 34.0 32 of 94 0.042
SGA history, % 32.7 16 of 49 24.7 19 of 77 0.220
Epo therapy, % 22.8 71 of 312 28.4 142 of 500 0.044
Iron therapy, % 32.7 102 of 312 35.4 160 of 500 0.448
Vit. D/calcimimetics/
phosphate binders, % 41.3 129 of 312 35.7 177 of 500 0.052
Acidosis therapy, % 40.8 125 of 306 40.5 201 of 496 0.493
Anemia, % 41.0 127 of 310 52.1 257 of 493 0.001
Non-repeated measure-
mentsaMedian (IQR) Min.–max No. of cases median (IQR) Min.–max No. of cases
Age at KT, years 4.26 (2.78–5.55) 1.35–7.73 52 of 52 3.68 (2.04–5.93) 0.49–7.98 94 of 94 0.529
Duration after KT,
years 7.51 (4.23–10.09) 0.06–10.88 52 of 52 8.33 (4.74–10.14) 0.06–10.93 94 of 94 0.608
Age at dialysis initia-
tion, years 2.05 (0.74–4.36) 0.01–7.40 35 of 52 1.92 (0.61–4.33) 0.01–7.81 63 of 94 0.956
Age at CKD stage 5,
years 2.94 (1.49–4.90) 0.01–7.40 52 of 52 2.98 (0.94–5.15) 0.01–7.87 94 of 94 0.851
Duration of dialysis,
years 1.47 (0.74–2.35) 0.01–4.71 36 of 52 0.78 (0.46–1.66) 0.03–4.75 64 of 94 0.011
Genetic target height,
SDS − 0.10 (–0.67–0.42) − 2.28–1.46 50 of 52 − 0.13 (–0.67–0.42) − 2.93–1.39 89 of 94 0.961
Menarche, age 11.79 (11.13–12.24) 10.74–12.97 8 of 20 13.02 (12.80–13.50) 10.21–13.70 7 of 44 0.040
Age at start of rhGH
therapy, years 1.93 (1.27–4.13) 0.27–6.31 52 of 52
Duration of rhGH
treatment, years 1.23 (0.59–2.23) 0.11–5.39 52 of 52
Repeated measure-
mentsbEstimated marginal
mean (95% CI) Min.–max No. of meas-
urements Estimated marginal
mean (95% CI) Min.–max No. of meas-
urements
eGFR, mL/min per
1.73 m2AA 71.21 (63.55–78.87) 4.74–147.40 301 of 312 59.20 (53.40–64.99) 8.53–190.54 474 of 500 0.018
Steroid dosage, mg/
kg per dayAA 0.04 (0.03–0.05) 0.00–0.33 303 of 312 0.06 (0.05–0.07) 0.00–0.49 476 of 500 0.016
Plasma HCO3,
mmol/LAA 22.39 (22.06–22.72) 18.53–31.55 304 of 312 22.72 (22.48–22.97) 18.30–28.32 476 of 500 0.106
Hb, g/dLAA 11.48 (11.20–11.76) 6.50–14.90 306 of 312 11.39 (11.15–11.63) 7.52–15.53 480 of 500 0.623
PTH, ng/l 89.00 (74.17–103.83) 1.12–641.30 259 of 312 89.80 (79.18–100.43) 5.50–708.00 420 of 500 0.930
CRP, mg/l 2.08 (1.39–2.76) 0.00–50.00 69 of 312 5.59 (2.62–8.57) 0.04–133.95 67 of 500 0.026
 Bone age delay, years –0.71 (− 1.05
to − 0.37) − 3.34–2.56 130 of 312 − 1.23 (− 1.51
to − 0.94) − 5.01–4.20 331 of 500 0.023

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Significant decrease of mean eGFR began in the non-
prior rhGH group 4years post-KT, whereas in the rhGH
group it began 8years after KT (each p < 0.01) resulting
in a substantially higher eGFR 10years after KT in the
latter group (69ml/min/1.73 m2 versus 46ml/min/1.73
m2, p < 0.01) (Fig.4). In both groups, post-transplant
eGFR was associated with time after KT, steroid dos-
age, and circulating hemoglobin levels (each p < 0.01,
Table3), whereas bicarbonate levels were positively
associated with post-transplant eGFR only in the non-
prior rhGH group (p < 0.05). The rhGH group had lower
steroid exposure than those without prior rhGH treatment
(p < 0.05) (Table1, Fig.5). Likewise, mean C-reactive
protein (CRP) levels were lower in the rhGH group
(2.08mg/l versus 5.59mg/l, p < 0.05). By contrast, mean
PTH and plasma HCO3 levels were comparable in both
groups (Table1).
Adjusted anthropometric z‑scores inpatients
withandwithoutprior rhGH treatment
After adjusting anthropometric data for potential con-
founders (including age at which CKD stage 5 was
reached, age at KT, average daily steroid dosage, pH
value, time after KT, and average eGFR, bicarbonate, and
hemoglobin levels during the preceding year), significant
differences between groups were limited to sitting height
z-scores (Table2).
Discussion
This study shows that treatment of children with rhGH in the
pre-transplant period was associated with several long-term
beneficial effects after transplantation, some of which were
unexpected. rhGH not only improved growth and matura-
tion after KT but was also associated with better long-term
transplant function, and lower degree of anemia and inflam-
mation. Our data confirm the limited potential for substantial
catch-up growth after KT and support the concept of timely
initiation of rhGH treatment prior to KT in children with
CKD and persisting short stature.
Growth failure is a hallmark of pediatric CKD, especially
CKD stage 5 [3, 25], as also exhibited in this young CKD
stage 5 population with mostly congenital CKD in which
short stature was noted in approximately 2/3 of patients.
In about 35% of patients, treatment with rhGH was com-
menced prior to transplantation due to persistent short stat-
ure as recommended by current guidelines [10, 26]. Con-
sequently, mean height z-scores at the time of KT did not
differ between children with or without prior rhGH treat-
ment. After KT, rhGH treatment was initiated in 18% of
patients without prior rhGH treatment but in none of the
rhGH group. Nevertheless, post-transplant growth was supe-
rior in the latter group. This is even more remarkable since
these patients, who spent longer time on dialysis and less
frequently underwent living related KT were burdened with
conditions associated with poor growth outcome [27, 28].
The prospective assessment of post-transplant changes
in linear body dimensions of both groups displayed dis-
proportionate short stature with predominant impairment
of leg length and rather preserved trunk length, which is
in line with previous studies [21]. This is known to result
in a significantly elevated sitting height index compared to
healthy children [2]. After KT, superior height gain in the
prior rhGH group occurred after an initial better preserva-
tion of sitting height followed by an improved long-term
catch-up growth with increasing leg length. We previously
demonstrated that KT preferentially stimulates trunk growth
in young children (age < 4years) and leg growth in older
children resulting in harmonization of body proportions
[8]. This reversible variation in the sizes of body segments
known as phenotypic plasticity seems beneficial for the
organism in adapting to changes in living conditions or ill-
ness [29]. The present study suggests that pre-treatment with
rhGH may prime the body to undergo phenotypic plasticity
after KT and thereby helps to harmonize body proportions in
these patients. As a consequence, the percentage of patients
with normal height after KT was substantially higher in the
rhGH group compared to that in the non-prior rhGH group
which was most pronounced at 7years after KT (88.9% ver-
sus 54.3%) corresponding to a mean age of 12years.
With the typical prepubertal peak of linear growth
occurring 1year later in the non-prior rhGH group, our
results suggest delayed onset of puberty and/or reduced
pubertal height gain in these patients. Similar differ-
ences were observed with respect to sexual maturation.
Menarche occurred timely in the rhGH group but was
delayed by approximately 1year in the non-prior rhGH
group. Previous studies showed that longer duration of
CKD, corticosteroid use, and lower GFR as well as shorter
stature were associated with delayed menarche [30], and
that girls with delayed menarche had lower bone mass den-
sity [31], which is in line with our results. Taken together,
our data suggest that pre-treatment with rhGH improves
growth as well as sexual and skeletal maturation after KT.
How does pre-treatment with rhGH impact on post-trans-
plant growth and maturation? Evidence in this regard comes
from two prospective studies investigating the effects of
rhGH treatment on bone histology and matrix mineralization
in short children on dialysis [32, 33]. Both studies showed
that rhGH not only improved growth in these patients, but
also normalized bone formation rates as well as bone matrix
mineralization irrespective of the type of histologic feature,
e.g., abnormal bone turnover, mineralization, and/or volume,

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Fig. 1 Mean hemoglobin blood
concentrations in 146 pediatric
kidney transplant recipients
with (solid lines, n = 52) and
without (broken lines, n = 94)
treatment with recombinant
human growth hormone (rhGH)
prior to kidney transplantation
(KT) during the pre-transplant
period. The label − 1 refers to
measurements collected in the
year prior to KT
Fig. 2 Post-transplant growth in 146 prepubertal children with (left,
n = 52) and without (right, n = 94) treatment with recombinant human
growth hormone (rhGH) prior to kidney transplantation (KT). Mean
z-scores for height, sitting height, and leg length are given. The
lower dotted horizontal line refers to the lower normal range (− 2.0
SD score). The label − 1 refers to measurements collected in the year
prior to KT

Pediatric Nephrology
1 3
whereas no such changes were noted in controls. Therefore,
pre-treatment with rhGH also might have improved bone
quality in the present study and thereby prepared the bone
for optimal post-transplant growth compared to patients
without prior rhGH treatment.
Other important factors known to affect post-transplant
growth including allograft function and steroid exposure
need to be considered as well. Long-term transplant func-
tion in pediatric kidney allograft recipients is influenced
by the quality of the transplant itself, with better results
with living related donors, recipient-related factors such as
HLA-matching and HLA-immunization and the immuno-
suppressive regimen [1, 34, 35]. In the present study, the
frequency of living related KT was lower in the rhGH group
compared to the non-prior rhGH group. This is most likely
due to the fact that patients for whom living-related trans-
plantation is not an option in the near future are known to
spend longer time on dialysis treatment [36], further exac-
erbating growth impairment. In those cases, physicians and
families are more likely to initiate rhGH treatment. Despite
this, long-term transplant function was superior in the
rhGH group compared to that in the non-prior rhGH group.
Table. 2 Nonadjusted and adjusted anthropometric parameters in prepubertal kidney allograft recipients who received rhGH before KT or not
A: Non-adjusted—Data are presented as SD scores (SDS), estimated marginal means (95% confidence intervals). p values are based on the lin-
early independent pairwise comparisons among the estimated marginal means
B: Adjusted—Data are presented as estimated marginal means (95% confidence intervals); age at chronic kidney disease stage 5, age at KT,
average daily steroid dosage in mg per kg per analyzed year, time after KT, pH values, hemoglobin average of last year, HC03 average of last
year and eGFR; p values are based on the linearly independent pairwise comparisons among the estimated marginal means
SDS standard deviation score, KT kidney transplantation, rhGH recombinant human growth hormone, eGFR estimated glomerular filtration rate
Parameter Stature SDS p value Leg length SDS p value Sitting height SDS p value Sitting height
index SDS p value
A Non-adjusted
rhGH prior to KT − 1.33 (− 1.58
to − 1.08) 0.049 − 1.47 (− 1.72
to − 1.22) 0.081 − 0.71 (− 0.95
to − 0.47) 0.026 1.20 (0.92 to 1.47) 0.937
No rhGH prior
to KT − 1.68 (− 1.92
to − 1.43) − 1.79 (− 2.04
to − 1.53) − 1.08 (− 1.31
to − 0.85) 1.18 (0.95 to 1.41)
B Adjusted
rhGH prior to KT − 1.34 (− 1.65
to − 1.03) 0.136 − 1.49 (− 1.76
to − 1.22) 0.154 − 0.67 (− 0.92
to − 0.41) 0.046 1.21(0.92 to 1.49) 0.849
No rhGH prior
to KT − 1.64 (− 1.90
to − 1.39) − 1.78 (− 2.08
to − 1.49) − 1.03 (− 1.28
to − 0.78) 1.24 (0.98 to 1.51)
Fig. 3 Mean bone age delay in
146 pediatric kidney transplant
recipients with (solid lines,
n = 52) and without (broken
lines, n = 94) treatment with
recombinant human growth
hormone (rhGH) prior to kidney
transplantation (KT). The
label − 1 refers to measurements
collected in the year prior to KT

Pediatric Nephrology
1 3
Fig. 4 Mean estimated glomeru-
lar filtration rates in 146 pediat-
ric kidney transplant recipients
with (solid lines, n = 52) and
without (broken lines, n = 94)
treatment with recombinant
human growth hormone (rhGH)
during the pre-transplant period.
The label − 1 refers to measure-
ments collected in the year prior
to KT. KT, kidney transplanta-
tion, eGFR, estimated glomeru-
lar filtration rate
Table. 3 Clinical predictors of transplant function
eGFR estimated glomerular filtration rate, KT kidney transplantation, CKD chronic kidney disease
AA Annual average
Parameter eGFR: rhGH prior to KT p value eGFR: No rhGH prior to KT p value
Age at stage 5 CKD (in year) 0.11 (− 4.56 to 4.79) 0.961 4.37 (− 3.99 to 12.72) 0.301
Age at KT (in years) − 1.59 (− 7.14 to 3.96) 0.567 − 5.90 (− 15.16 to 3.35) 0.209
Time after KT (in years) − 2.96 (− 3.69 to − 2.23) 0.000 − 2.39 (− 2.75 to − 2.02) 0.000
Steroid dosage (in mg/kg) − 99.14 (− 133.20 to − 65.09) 0.000 − 60.92 (− 87.03 to − 34.81) 0.000
Hemoglobin (in 10* g/dl)AA 4.27 (2.79 to 5.75) 0.000 1.84 (0.77 to 2.92) 0.001
Plasma HCO3 (in 10*mmol/l)AA 0.03 (− 1.08 to 1.14) 0.957 0.85 (0.11 to 1.59) 0.024
Fig. 5 Mean daily prednisolone
dosages in 146 pediatric kidney
transplant recipients with (solid
lines, n = 52) and without
(broken lines, n = 94) treat-
ment with recombinant human
growth hormone (rhGH) prior
to kidney transplantation (KT).
The label − 1 refers to measure-
ments collected in the year prior
to KT

Pediatric Nephrology
1 3
Although, in this observational study the primary immu-
nosuppressive regimens did not generally differ between
patients with or without prior rhGH treatment, the latter
group received a substantially higher steroid exposure,
which may at least partly explain the inferior growth out-
come in this group. Lower steroid exposure in the rhGH
group may be the consequence of better graft function facili-
tating steroid minimizing/withdrawal in these patients.
Elevated CRP levels were noted in the non-prior rhGH
group but not in the rhGH group. C-reactive protein is
a marker of the acute phase response to inflammation.
Elevated circulating CRP (> 3mg/L) is associated with
accelerated deterioration of graft function in kidney trans-
plant recipients and thought to reflect kidney inflammation
due to subclinical rejection [37–41]. Therefore, the notion
of significantly elevated CRP levels in the non-prior rhGH
group may not only explain the higher frequency of ane-
mia as a consequence of inflammation but also subclinical
graft rejection in these patients which may contribute to
the inferior long-term graft function.
Finally, growth hormone and its mediator insulin-like
growth factor (IGF) 1 play an important role in immu-
noregulation. Immune cells such as T and B lymphocytes
express GH and IGF receptors and are therefore targets
of both GH and IGF1 which may act as local growth and
differentiation factors [42] and may regulate cytokine
reaction [43]. However, a meta-analysis found no elevated
rejection rates or more rapid deterioration of graft function
due to rhGH treatment in pediatric kidney allograft recipi-
ents [44]. Data on the immunomodulatory effects of rhGH
in pediatric CKD patients prior to KT are lacking. In view
of the superior graft function in patients with prior rhGH
treatment in the present study, it is tempting to specu-
late that pre-treatment with rhGH might have modified
the immune response to the kidney allograft positively.
However, several potentially confounding factors such as
HLA mismatch, HLA antibodies, non-steroid immunosup-
pressive therapies, and allograft biopsy results could not
be addressed in our study. An analysis with inclusion of
patients who received rhGH before, as well as after KT
was performed in which there was no marked difference
to the analysis which excluded those patients, possibly due
to the small number of those patients (n = 9). Therefore,
a dedicated analysis regarding impact of and reasons for
rhGH treatment in patients before, as well as after trans-
plantation, is an interesting subject for further research.
In conclusion, pre-KT rhGH treatment in pediatric
kidney allograft recipients resulted in superior long-term
growth outcome after KT compared to patients without
prior rhGH treatment which was mainly due to improved
leg growth as well as skeletal maturation. Our data sug-
gest that treatment with rhGH in the pre-transplant period
in CKD patients presenting with persistent short stature
is not only useful to improve growth outcome, but rather
induces manifold positive effects such as lower rates of
inflammation and anemia as well as better preservation of
transplant function.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00467- 021- 05222-5.
Acknowledgements We thank the patients and their families taking
part in this study and appreciate the support of doctors and nurses
responsible for patient care.
Author contribution M. Ž., C. J., and D. H. designed the study. M.
Ž. performed anthropometric measurements. M. Ž., C. J., and L. P.
performed the statistical analysis and interpreted the data. C. J., R.
K., S. M., and M. Ž. collected clinical data. C. J., R. K., S. M., and
M. Ž. wrote the first draft of the manuscript; M. Ž. and D. H. revised
the manuscript. All authors critically reviewed the manuscript and
approved the final version for publication.
Funding This study received internal funding from Hannover Medi-
cal School. The funder had no influence on the content of this study.
Data availability Data cannot be published as it is used in an ongoing
study.
Code availability Not applicable
Declarations
Conflict of interest The authors declare no competing interests.
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/.
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