Growth retardation after pediatric kidney transplantation (KT) is multifactorial and influenced by the degree of pretransplantation growth deficit, primary renal disease, presence of comorbidities, age at KT, graft function and steroid exposure which interfere with the growth hormone/insulin-like growth factor 1 axis.1,2 In adults who were transplanted during childhood, short stature has a significant impact on social and work life.3,4 Moreover, it has been reported that more than one-third of young adults with childhood-onset end-stage kidney disease (ESKD) were dissatisfied with their body height.4 Given the consequences of short stature on quality of life and self-esteem, achieving a normal height is a crucial issue for pediatric kidney transplant recipients. Improvements in the management of growth impairment have led to a decreased prevalence of growth failure at KT, but catch-up growth post-KT is generally not sufficient to compensate for the deficit that has been acquired before transplantation.5,6 The height SD scores (SDS) of North American pediatric kidney transplant recipients was −1.75 at the time of KT and remained relatively constant at follow-up.5 Among those reaching adulthood, the mean height SDS was −1.4 with 25% having a SDS <−2.2.5 The European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry reported that although there was a trend toward consistent improvement of adult height after KT in childhood over time, only a slight majority of patients (57%) achieved a final height within the normal range (height SDS ≥ −1.88).7 In Europe, data evaluating the effect of KT on growth are limited to single-center studies. Therefore, in this large population-based European study, we aimed to describe the pattern of changes in height SDS after KT, to identify potential determinants of height SDS, and to investigate growth associated outcomes.
MATERIALS AND METHODS
For this study, we used data recorded within the framework of the ESPN/ERA-EDTA Registry. As previously described,8,9 the Registry collects individual patient data annually through national pediatric registries on the date of birth, sex, primary renal disease, treatment modality, and dates of change in treatment modality of all European children requiring renal replacement therapy (RRT) and a variable set of anthropometric, clinical and medication-related parameters. We included patients who received a KT at <18 years of age between January 1990 and December 2012, and with at least 2 height measurements available until the age of 21 although living with a functioning graft. This included data from 23 European countries out of the 37 participating in the ESPN/ERA-EDTA Registry. The national legislation with regards to ethics committee approval and informed consent was followed for all national registries providing data to the ESPN/ERA-EDTA Registry.
We selected data on KT and era of KT, donor source, height SDS at KT and subsequent height SDS measurements, estimated glomerular filtration rate (eGFR), use of steroids, hemoglobin level, and blood pressure.
Definition of Variables
Height SDS was calculated based on recent national growth charts whenever available, or on newly developed northern and southern European growth charts.10 Height SDS values were calculated by the following equation: SDS = (individual patient value − mean value for age and sex-matched healthy peers)/SD value for age and sex-matched healthy peers.
Growth deficit was defined as a height SDS <−1.88 SDS and was considered as moderate (−1.88 > SDS > −3) or severe (<−3 SDS). Height at KT was defined as the closest available height measurement within 6 months before or after KT, or within 3 months for those who were transplanted before 2 years of age.
The eGFR was calculated using the adjusted Schwartz formula.11 Hypertension was defined as either systolic or diastolic blood pressure ≥95th percentile for age, height, and sex or use of antihypertensive medication.12 Based on the The National Institute for Health and Care Excellence (NICE) UK clinical guidelines on anemia, we defined anemia as an hemoglobin level <10 g/dL, or <9.5 g/dL for children younger than 2 years.13 Renal diseases were grouped by primary renal disease code for pediatric patients, according to the ERA-EDTA Registry coding system.14 As there were no major advances in the field of pediatric KT since the approval of tacrolimus and mycophenolate mofetil in the 1990s, we decided to categorize the variable “era of KT” by decade. However the follow-up time did not enable us to study 30 years of follow-up, and therefore, the most recent period consisted of only 3 years. This led to unbalanced groups because most patients were included in the ESPN/ERA-EDTA Registry after 2000.
General characteristics of the population were presented as median, interquartile range (IQR) and range for continuous variables, and as percentages for categorical variables. Because of multiple height measurements per patient were available, we applied linear mixed model regression analyses with both a random intercept and a random slope to correct for correlation of measurement within a patient resulting in an average post-KT height SDS. Height data were smoothed using a 3-degree polynomial spline function. To calculate the prevalence of growth deficit after KT, we used multinomial generalized estimating equation models. Factors associated with mean height SDS and the relationship between change in height SDS over time and potential associated factors were investigated. Analyses were adjusted according to the criteria for confounding.15 Variables considered in the adjusted analyses were age at KT, sex, height SDS at KT, primary renal disease, donor source, number of KT, era of KT, and duration of RRT. Time-varying covariates included time since KT, eGFR, hypertension, anemia, and exposure to steroids. Missing values were imputed using a multiple imputation approach as recommended by the STROBE guidelines.16 Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).
Baseline Population Characteristics
Data on growth were available for 3492 patients who received a kidney transplant from 23 countries resulting in a total of 23 207 measurements (median per patient: 4, IQR: 2–7). During follow-up, 3718 KT were performed. Median age at KT was 10.5 years (Table 1), most often performed in males (60%), and from a deceased donor (64%); peritoneal dialysis (44%) was the most frequent treatment modality at the start of RRT. KT was performed preemptively in 29%. Congenital anomalies of the kidney and urinary tract (CAKUT) were the most common cause of ESKD (46%), followed by glomerulonephritis (13%). Median height SDS at the time of KT was −1.87 (IQR: −2.81 to −0.97), which is equivalent to the third percentile for same sex and age peers.
Mean Height SDS and Prevalence of Growth Deficit
After adjustment for sex, primary renal disease, age at KT, time since KT, and period of KT, the overall mean height SDS post-KT in the total cohort was −1.77 ± 0.04. Overall, 55.1% of children (95% confidence interval [CI]: 53.7-56.4) had a height SDS within the normal range post-KT (ie, >−1.88), 28.0% (95% CI: 27.0-29.1) showed moderate growth deficit, and 16.9% (95% CI: 16.0-17.9) exhibited severe growth deficit. The proportion of pediatric transplant recipients with a normal height was slightly higher in boys (56.7%) than in girls (52.5%).
Factors Associated With Posttransplant Height
Factors associated with posttransplant height are depicted in Table 2.
Living kidney donation, preemptive KT or dialysis for <1 year before KT, steroid-free immunosuppressive regimen, higher eGFR, and not being hypertensive or anemia were associated with a better posttransplant height SDS. Moreover, after adjustment for sex, age at KT, period of KT, and time since KT, patients with CAKUT were significantly shorter than those with glomerulonephritis, hemolytic uremic syndrome, vasculitis, and those with miscellaneous or unknown causes of renal failure, whereas patients with metabolic disorders were significantly shorter than CAKUT patients (Table 2). A more recent period of transplantation was not associated with a better posttransplant height SDS. Children who received a deceased donor KT were shorter by 0.15 SDS at transplant and tended to show a somewhat lower catch-up growth posttransplant than those transplanted with a living donor (+0.35 SDS deceased versus +0.39 SDS living) (Figure 1).
Age and Sex Differences in Posttransplant Growth
There were large age differences in posttransplant growth (Figure 2). Although children under the age of 6 years at KT had the largest height deficit at the time of transplantation, they showed the greatest increase in height SDS: +0.67 SDS in children under 3 years and +0.8 SDS in children transplanted between 3 and 6 years. Limited growth was observed in children transplanted between the ages of 6 and 12, whereas there was no catch-up growth in children who were older than 12 when transplanted.
After adjustment for age at KT, period of KT, and time since KT, girls (−1.84 SDS) had a significantly lower height SDS than boys (−1.73 SDS). Further adjustment for primary renal disease and time on dialysis before KT did not change this association (height SDS −1.71 [95% CI: −1.80 to −1.61] and −1.85 [95% CI: −1.94 to −1.77] in boys and girls, respectively). Catch-up growth was observed in both sexes (+0.37 SDS in boys and +0.33 SDS in girls), but since the height, SDS of boys at KT was significantly higher than that of girls their height SDS remained higher during 5 years of follow-up (Figure 3). We observed age differences in posttransplant growth for both sexes. When transplanted below 6 years of age, the height at KT was not different for boys and girls, but the 5-year change in height SDS was larger among boys than among girls. The adjusted height SDS of boys transplanted between 6 and 12 years increased from −1.96 to −1.61 at 5 years posttransplant (+0.35 SDS) and from −2.32 (−2.53 to −2.12) to −1.96 (−2.13 to −1.79) (+0.36 SDS) in girls. There were no sex differences in adolescents, both with respect to the height at KT, and the height during follow-up.
Trend Over Time
No significant difference in height at KT or in posttransplant growth was observed according to the period of KT (1990–1999, 2000–2009, and 2010–2012) (Figure 4).
Short stature is present in nearly half of pediatric kidney transplant recipients in Europe. Catch-up growth post KT remains limited and is mainly observed in the youngest recipients and those with (preemptive) living donor KT. We found no substantial improvement in growth post-KT over time. At transplant, about half of the transplant recipients had a short stature or were shorter than the third percentile of their peers, suggesting that prevention of chronic kidney disease (CKD)-related growth retardation in the pretransplantation phase of the disease has remained insufficient in the past 25 years in Europe, despite the possibility for optimal nutrition, correction of hyperparathyroidism and metabolic acidosis, and the availability of recombinant human growth hormone (rhGH) therapy in most European countries.
According to the North American Pediatric Renal Trasplant Cooperative Study (NAPRTCS) 2014 annual report, the average height SDS at KT in North American pediatric recipients was −1.73 (ie, below the fourth percentile for age and sex).17 In concordance with the NAPRTCS, the mean height SDS remained relatively constant at −1.77 SDS over the available posttransplant follow-up, demonstrating that even successful KT fails to provide significant catch-up growth in the majority of recipients. However, post-KT growth patterns largely differed by age. The youngest recipients (<6 y) had the greatest height deficits at KT but experienced a posttransplant height increase of 0.7–0.8 SDS, which resulted in normal height attainment in most of them. Conversely, children who were 6–12 years of age showed very limited catch-up growth during the first 2 years posttransplant, and those older than 12 years at KT experienced no increase or even a slight decrease in height SDS averaging at about −1.7 SDS. Other registry data and single-center studies already suggested that catch-up growth after KT was restricted to children under 6 years of age.2,18,19 Conversely, previous reports, mostly from centers with a special interest in growth, reported substantial, and sometimes impressive, catch-up growth in prepubertal children who were under 12 years of age.20-22 However, data from clinical trials appeared to be less encouraging than the aforementioned reports and showed limited catch-up growth in prepubertal children and no catch-up growth in pubertal children.23,24 Except in a few studies,20,25 poor linear growth is usually observed in pubertal children and KT during adolescence does not allow catch-up growth. A delayed onset and shorter duration of the pubertal growth spurt resulting in decreased pubertal height gain, and the strong negative effect of low eGFR in this age group, may explain the poor growth outcome of children transplanted after 12 years of age.
Additionally, we identified several other factors associated with height SDS in this study: sex, primary renal disease, graft function, blood pressure, anemia, and exposure to steroid therapy. Contrary to the NAPRTCS, we found that at KT, the height deficit in girls was larger than in boys and remained larger during posttransplant follow-up. A previous study in children with CKD stage 3–5 also reported that height deficit was more pronounced in girls than in boys.26 In our study, the sex difference in height at KT and post-KT was mainly found among those transplanted at 6–12 years. Although difficult to explain, one could speculate that girls are referred later than boys in the course of the disease,27 or that growth impairment during the CKD phase before KT is less aggressively managed (including use of rhGH) in girls than in boys. Furthermore, expressing height according to chronological age rather than according to bone age or pubertal stage might have contributed to our findings of superior growth in boys. Consistent with other studies,26,28 we found that congenital primary renal diseases (CAKUT and hereditary nephropathies) were associated with shorter stature than glomerular and vascular diseases, possibly because of a longer duration of the CKD period, and the role of salt wasting and metabolic acidosis which are involved in growth failure. Not surprisingly, anemia, hypertension, and eGFR <30 mL/min/1.73 m2, all indicating poor graft function, were also associated with a reduced height SDS as in previous reports.28-30 Similar to CKD, GFR is a major determinant of growth after KT and final height.31 Indeed, prepubertal catch-up growth and total pubertal height gain correlated positively with GFR.20 We further found that patients who received a living donor kidney had a significantly greater height SDS at KT and tended to have a better growth during the 5-year posttransplant follow-up than those who received a deceased donor graft. A remarkably similar finding has been reported in a single-center study in Germany,32 and we previously reported that preemptive KT or a short period of dialysis was associated with better final height SDS.7 Finally, a steroid-free immunosuppressive regimen was significantly associated with height SDS in the present study. Growth depression is a well-known side effect of corticosteroid therapy and is partially mediated by alterations in the somatotropic hormone axis.1 Several recent randomized controlled trials and observational studies showed that steroid withdrawal/avoidance was associated with a significant increase in growth compared with remaining on steroids. Although the effect is mild (mean difference in height of 0.2–0.3 SDS) and restricted to prepubertal children,33 steroid withdrawal/avoidance regimens seemed to be safe and not associated with acute rejection, graft failure or death, at least in the first years posttransplant.33 In this registry study, the use of steroids decreased by 20% over time, and the overall mean difference of 0.2 SDS in steroid-free immunosuppressive regimen is in line with the findings of randomized trials.
Contrary to findings in the United States,2 we did not find any improvement in posttransplant height SDS over the last 20 years. The average height deficit of United States children transplanted 25 years ago (−2.43 SDS in 1987) was larger than in Europe. However, in 2009, the average height SDS at KT in United States patients was with −1.23 SDS, considerably higher than in Europe. Although we used recent national growth charts to account for the secular trend in height, it should be noted that the growth charts used in the NAPRTCS study are based on data collected 40 years ago. Applying these US growth charts resulted on average in a 0.36 higher height SDS compared to recent national or European growth charts,10 and use of different growth charts could possibly explain some of the differences in post-KT height between Europe and the United States. Despite the lack of improvement in post-KT height SDS in this study, in a previous registry study, we reported an increase in final height over time.7 However, as height SDS did not significantly change between RRT initiation and final height measurement, the improvement of final height over time was most likely because of better growth management in the pre-ESKD period, which might also explain the lack of improvement in post-KT growth. Moreover, during recent years more severe and difficult to manage patients are accepted into RRT programs, and although we adjusted our analyses for differences in patient characteristics, some residual confounding due to unmeasured case-mix differences might still be present. Nevertheless, it is quite worrisome that post-KT growth in Europe has not improved since the early 1990s, particularly given the implications of short stature on quality of life and a variety of options to improve it.
Further improvement in post-KT growth might be expected by promoting living-donor and preemptive KT; steroid withdrawal/avoidance immunosuppressive regimen, particularly in prepubertal children33; and possibly more regular use of rhGH. A study by van Huis et al34 showed that only 22% and 6% of short patients on dialysis and after KT, respectively, received rhGH in Europe, and this was not restricted to lower income countries. Rather than by any financial hurdles, the actual prescription of rhGH seemed to be more determined by physician’s and patient’s attitudes towards rhGH therapy.34 Moreover, a recent US study reported that height gains with rhGH among pediatric CKD patients with short stature were associated with better parent-reported physical and social functioning.35
The strengths of our study include the large population, the long follow-up period and repeatedly measured height values, covering patients treated in 23 different European countries. However, some limitations of our work need to be acknowledged. Detailed data on factors affecting growth, such as nutritional status, control of metabolic acidosis and mineral bone disorders, pubertal status, bone age, birth weight, and comorbid conditions, were not available from the ESPN/ERA-EDTA Registry. In addition, the reported medication use (ie, steroids, rhGH) was very limited, and we were not able to adjust our analyses for medication use.
To summarize, growth after pediatric KT in Europe remains suboptimal, with a short stature in almost half of the patients. Catch-up growth is restricted to the youngest recipients and there was no substantial improvement over time. Early, preferably preemptive transplantation with a graft from a living donor, in combination with steroid avoidance/withdrawal immunosuppression regimens, more regular application of rhGH, and maintaining an optimal graft function could possibly lead to improvements in growth.
We would like to thank the patients, their parents and the staff of all the dialysis and transplant units who have contributed data through their national registries and contact persons. We also would like to thank E. Levtchenko, D. Haffner, Z. Massy, and C. Stefanidis for being members of the ESPN/ERA-EDTA Registry Committee, D. Shtiza, R. Kramar, A. Sukalo, K. van Hoeck, and the Centre contributors to the Belgian Registry Committee, D. Pokrajac, D. Roussinov, D. Batinić, M. Lemac, J. Slavicek, D. Milosevic, A. Elia, T. Seeman, K. Vondrak, J.G. Heaf, Ü. Toots, P. Finne, A. Pylsy, P.-H. Groop, C. Couchoud, M. Lassalle, E. Sahpazova, N. Abazi, T. Davitaia, K. Rascher, E. Nüsken, L. Weber, G. von Gersdorff, J. Dötsch, F. Schaefer, K. Krupka, B. Höcker, B. Tönshoff, N. Afentakis, A. Kapogiannis, N. Printza, G. Reusz, C.s. Berecki, A. Szabó, T. Szabó, A. Barczi, O. Lakatos, E. Kis, V. Edvardsson, B. Gianoglio, I. Guzzo, B. Minale, R. Roperto, E. Vidal, E. Verrina, H. Čerņevskis, V. Kuzema, S. Rudaitis, A. Jankauskiene, V. Said-Conti, S. Gatcan, O. Berbeca, N. Zaikova, N. Revenco, S. Pavićević, A. Åsberg, A.V. Reisæter, A. Zurowska, C. Mota, R. Stone, C. Afonso, G. Mircescu, E.A. Molchanova, N.A. Tomilina, M. Kostić, B. Spasojević, M. Cvetković, I. Gojković, D. Paripović, G. Miloševski-Lomić, L. Podracka, G. Novljan, J. Buturovic-Ponikvar, A. Alonso Melgar, and the Spanish Pediatric Registry, K.G. Prütz, M. Stendahl, M. Evans, S. Schön, M. Segelmark, T. Lundgren, G.F. Laube, C.E. Kuehni, H. Chehade, C. Rudin, and the Swiss Paediatric Renal Registry, L. Heuveling and M.H. Hemmelder on behalf of the Nefrovisie foundation, and all centers participating in the RichQ-study, D.D. Ivanov, S.P. Fomina, F. Braddon, A. Casula, and L. Plumb for contributing data to the ESPN/ERA-EDTA Registry.
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