1 Background

Short stature is a common sequela of chronic kidney disease (CKD) which begins in childhood. Data from the European Society for Pediatric Nephrology (ESPN)/ERA-EDTA Registry indicated that 62% of boys and 41% of girls who started renal replacement therapies (RRT) for end-stage kidney disease (ESKD) before the age of 15 years, reached their final height (FH) at more than two standard deviations (SD) below the normal mean, that is, <3rd percentile [1], and data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) showed that the mean baseline height standard deviation score (SDS) of kidney transplant (KT) recipients, was −3.34 at the time of transplantation [2].

The short stature in patients with CKD has profound life-long negative consequences. It has been associated with a negative effect on quality of life [3]. It may lead to low self-esteem, anxiety and depression, lack of participation in extracurricular activities, relationships, emotional and developmental challenges, decreased educational achievements [4] and workplace success [5], and even increased mortality [6]. Therefore, achieving as close to a normal final adult height is crucial for children with CKD.

The cause of the impaired growth in children with CKD was thought to be multifactorial, related to the age of onset of the renal insufficiency, acidosis, fluid and electrolyte abnormalities, inadequate nutrition, bone disease of CKD, and hormonal and growth factors abnormalities, especially dysregulation of the growth hormone (GH) and insulin-like growth factor (IGF) axis [7]. However, despite improved and optimal clinical management of these potential causative factors, including optimizing nutritional intake by tubefeeding, children with advanced chronic renal failure from an early age did not achieve catch-up growth [8].

With the advancements made in the 1990s, both in the technical aspects of KT in children as well as in the immunosuppressive regimens, an improvement in growth after successful renal transplantation was anticipated. However, data from the NAPRTCS revealed that only 30%–50% of children had improvement in growth [2], and only children who received a KT before the age of 6 years, demonstrated catch-up growth [9]. Studies from Europe found that the post-KT growth was best in the patients with the worst height SDS at the time of their first KT; however, the better catch-up growth after KT did not compensate for the severe growth retardation, and 71%–77% of patients who received their first KT before the age of 15 years ended up with severely short adult stature [10].

Other than the age at kidney transplantation, the main factors affecting children's growth after KT are corticosteroid treatment and the allograft function. Studies of spontaneous GH secretion in 40 pubertal KT recipients showed an inverse relationship between the peak GH amplitude and corticosteroid dosage, indicating that the pubertal growth failure in KT recipients was, at least partly, a result of GH hyposecretion related to corticosteroid treatment [11].

Further investigations into the relationship between corticosteroid doses and post-KT growth have shown that early decrease in steroid dose, steroid withdrawal, and steroid avoidance are associated with improved growth after KT [12-14]. However, there are significant differences in the practice of steroid avoidance among transplant centers and most KT recipients in childhood are treated with steroids during the life of their KT [15].

Another important factor associated with decreased growth velocity after KT is reduced renal allograft function. Recipients who have an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² have a reduced height SDS compared to children with a higher eGFR [16]. The superior growth outcome observed in children undergoing preemptive or living donor KT reported in some studies, is thought to be due to better graft function, lower steroid exposure, and better preserved growth at the time of KT in these patients, rather than to prior dialysis treatment or the allograft source. In the few studies, examining the efficacy of recombinant human growth hormone (rhGH) treatment post-KT in which the percentage of living-related donor versus cadaveric donor recipients is indicated, there is no differentiation of growth outcomes between the two groups [16, 17].

After childhood dialysis and KT became life sustaining treatments in children with CKD, increasing emphasis was placed on efforts to treat and prevent the stunted growth of these patients.

2 Human Growth Hormone as Treatment of Growth Retardation in Childhood CKD

Endogenous GH deficiency was shown not to be the pathogenesis of the stunted growth of children with CKD [18]. In fact, children with CKD were found to have increased levels of serum GH and insulin growth factor-I (IGF-I) [19]. Despite the finding that GH and IGF-I levels were normal or even elevated in uremia, studies by Mehls et al. [20] in uremic rats in the 1980s, demonstrated improved body length when the rats were injected with supraphysiologic doses of rhGH. These discoveries prompted an initiation of a series of pilot studies at UCLA, to evaluate the efficacy and safety of rhGH in children with CKD prior to dialysis, those treated with dialysis, and in a group of patients who had undergone a successful renal transplantation. These preliminary studies demonstrated the efficacy of rhGH therapy in improving height SDS over baseline most effectively in the patients in the earlier stages of CKD [21], but also in a group of 13 pediatric posttransplantation patients. In this pilot study, the improvement in growth velocity and height SDS values persisted in the first 2 years of treatment. No increase in acute rejection episodes was seen in the small group of KT recipients during the rhGH treatment period compared with the same posttransplant interval prior to the initiation of the rhGH treatment [22]. Soon after these early reports, Hokken-Koelega et al. [23] reported results of a double-blind, placebo-controlled, 6-month crossover trial of rhGH in 11 prepubertal KT recipients. The participants in the trial were at least 12 months posttransplantation, with a height SDS worse than −1.88 and a bone age (BA) <10 years for the two girls, and <12 years for the nine boys. The results of this study demonstrated significantly improved height velocity in the children who started the trial with rhGH therapy compared with those who started the study receiving placebo.

3 Potential Adverse Effects (AEs) of rhGH Treatment in Pediatric CKD Patients and KT Recipients

The potential AEs of rhGH were of concern prior to the initiation of the aforementioned phase I trials conducted in the late 1980s. The main concerns were whether rhGH would accelerate the BA beyond the chronological age (CA) leading to earlier fusion of the growth plates, thereby denying the patients the potential for further growth. Additional concerns were: (1) whether rhGH would lead to glucose intolerance and perhaps diabetes mellitus, especially in post-KT recipients treated with corticosteroids and calcineurin inhibitors, (2) whether it might accelerate the decline in renal function, or (3) whether in post-KT recipients, it would increase the rate of acute rejection episodes. Other concerns were the potential for increased intracranial pressure, increased incidence of slipped capital femoral epiphysis (SCFE), and worsening of other bone disease in CKD and post-KT patients. Therefore, these potential side effects were prospectively assessed in the children enrolled in the initial Phase I study. In preliminary reports, BA advancement was consistent with the period of growth. Laboratory determinations, including results of glucose tolerance testing, did not vary significantly from pretreatment levels, nor were there any other complications of note [24, 25].

Eleven patients with CKD enrolled in the original Phase I study prior to renal replacement therapy (RRT) [26] were followed for a longer period of time (18–72 months). Six of the 11 patients were treated with rhGH for more than 5 years, and one patient was treated for 96 months. Only after 5 years of rhGH treatment was there a statistically significant difference in kidney function compared with baseline which was similar to the natural course of CKD at the time, indicating that long-term treatment of children with CKD did not accelerate the decline in kidney function. The fasting and 2-h postprandial blood glucose values did not differ from baseline values. Although 2-h postprandial insulin levels did occasionally increase modestly over baseline values during the follow-up period, in those patients treated for ≥5 years, the values were similar or even lower than baseline values. Thus, there was no evidence that long-term rhGH treatment in children with CKD led to glucose intolerance. There were no instances of slipped capital femoral epiphysis, avascular necrosis, increased intracranial pressure, or de novo malignancies in any of the patients in the Phase I study treated with rhGH for ≥5 years. In the long-term follow-up of the 13 pediatric allograft recipients enrolled in the phase I trial [27] no increase in acute rejection episodes was seen during the treatment period with rhGH compared with the same posttransplant interval prior to the initiation of the rhGH treatment. Only two of the subjects had an increase in their BA of 0.5 year above the progression in their CA. In the remaining 11 KT recipients, the mean BA did not increase more than the increase in CA. Similarly, in the double-blind, placebo-controlled, 6-month crossover trial of rhGH in 11 prepubertal KT recipients conducted by Hokken-Koelega et al. [23], bone maturation was not accelerated, acute renal graft rejection did not occur in any of the patients, and the mean GFR and effective renal plasma flow did not change significantly during rhGH therapy. In this study, rhGH induced a significant increase in the mean plasma insulin levels during oral glucose tolerance test, however, it did not change plasma glucose levels. Serum parathyroid hormone levels remained stable. The same group of researchers then followed 45 Dutch prepubertal children (28 boys, 17 girls) with CKD and severe growth retardation who were on rhGH therapy between 1988 and 1991 for a maximum of 8 years, showing a sustained and significant improvement of height SDS compared with baseline values without the bone maturation accelerating beyond the CA or radiological signs of renal osteodystrophy. Furthermore, there was no evidence of accelerated deterioration of the renal function [28].

The results of the pilot studies led to a Federal Drug Agency (FDA) directed multicenter, randomized, placebo-controlled, double-blind study to determine whether rhGH treatment of growth-retarded children with CKD enhances growth rate, and at the same time, whether there were AEs on bone maturation, CKD progression rate, and glucose levels in the treated group [29]. One hundred and twenty-five patients with a mean height SDS worse than −1.88, from 17 pediatric nephrology centers in the United States, were enrolled in the study between 1988 and 1990. A third of the subjects received placebo subcutaneous injections and two-thirds received rhGH injections for a period of 2 years. The two groups were matched for height SDS, GFR, BA, and causes of their primary renal disease. The rhGH-treated group showed significantly improved growth rates during the 2-year study, whereas the height SDS of the placebo group remained <−1.88. There was no acceleration in the BA compared with the CA, no significant difference in the change in eGFR from baseline compared with that in the placebo group, and mean fasting and 2-h postprandial glucose values were not significantly elevated over baseline values in either group [29]. These results led to the FDA approval of the use of rhGH to treat the short stature of children with CKD and ESKD, but not of short children who were KT recipients. Multiple researchers around the world embarked on studying the efficacy and safety of rhGH treatment of children with short stature after undergoing successful KT. Data on 2390 transplant recipients in the National Cooperative Growth Study (NCGS) linked to the database of the NAPRTCS demonstrated increased growth in the KT recipients treated with rhGH for up to 3 years without a decrease in graft survival or function, and with no increase in acute rejection episodes [30]. A 2-year prospective, controlled study in Europe, carried out at 18 French pediatric centers, demonstrated improved growth velocity in KT recipients who were treated with rhGH. Increased incidence of rejection was seen only in patients with a prior history of more than one rejection episode [31]. In 2000, Fine et al. [32] evaluated the impact, from transplant to 60 months, of rhGH treatment on a cohort of 102 pediatric KT recipients who were treated with rhGH during the course of their pretransplant CKD (cohort) and compared it with data from 4913 KT recipients from the NAPRTCS database who were not treated with rhGH prior to receiving the KT (control group). The parameters evaluated included growth, patient and graft survival, time to first acute rejection episode, causes of graft failure, and adverse events. This comparison demonstrated an improvement of the height SDS in the cohort of KT recipients who had been treated with rhGH during their CKD course, versus a slight worsening in the height SDS of the control group. No significant differences were found in patient and graft survival, incidence of acute rejection episodes or adverse events attributable to the pre-KT rhGH treatment between the two groups. Only two patients in the cohort group developed posttransplant lymphoproliferative disorder [32]. In order to try and delineate the immunomodulation effect of rhGH in KT recipients, as well as to determine the impact of rhGH on graft function and other adverse risk factors, the NAPRTCS undertook a multicenter, randomized controlled study of the use of rhGH in growth-retarded children with KT, with protocol biopsies prior to randomization and repeated biopsies thereafter. Sixty-three renal allograft recipients from 18 NAPRTCS participating centers were randomized to either a 1-year treatment group (N = 36) or a control group (N = 27). The control group received no treatment for 1 year and then was offered rhGH treatment. Both groups were followed for a total of 30 months of rhGH treatment. In the control group, three de novo rejection episodes were confirmed by biopsy during the first study year, whereas no rejection was noted in the treatment group [33].

Recently, Jagodzinski et al. [34] analyzed growth and clinical parameters data in patients from two pediatric nephrology centers in Germany, who received a KT before the age of 8 years. They compared those who received rhGH prior to the KT, at which time the rhGH treatment was discontinued, with those who were not treated with rhGH prior to receiving a KT. The pre-KT rhGH-treated group had improved growth, as well as a significantly better GFR at 10 years post-KT, even though they had a lower incidence of living-related transplantations. The pre-KT rhGH-treated group also had lower corticosteroid exposure, but despite that, they had lower inflammatory markers and less anemia than observed in the non-rhGH-treated group. In 2013, Wu et al. [35] published a meta-analysis of five randomized, controlled trials (RCTs) of rhGH treatment in short KT recipient children, concluding that growth hormone improves stature growth in pediatric renal transplant recipients, with inconsistent and contradictory results of the effects of growth hormone on renal function and rejection rates.

4 Final Adult Height

The question of whether the KT recipients treated with rhGH in childhood achieved a normal or improved final adult height remained unanswered until cohorts of these patients reached their FH. Because the majority of the patients enrolled in the early studies on the effect of rhGH treatment on height in KT recipients were younger than 12 years of age at the time of transplant, it was not possible to assess their final adult height [32]. These data only became available when studies and follow-up assessments on rhGH treatment were continued until subjects reached their final adult height.

Haffner et al. [36], describing the results from the German Study Group For Growth Hormone Treatment in Chronic Renal Failure in 2000, reported on 38 patients with CKD who were treated with growth hormone from a mean age of 10.4 ± 2.2 years until they reached their final adult height. These patients were compared to 50 matched children with CKD who were not treated with growth hormone. The growth hormone-treated children, including nine KT recipients, experienced sustained catch-up growth, with the majority of them achieving normal adult height, whereas the control children had progressive growth failure. In this study, bone maturation accelerated slightly during the prepubertal period in the growth hormone-treated children, as compared to the control children, however, the total height gain during the prepubertal observation period was approximately twice as great in the growth hormone-treated children as in the control children group, sufficient to override the adverse effect of accelerated skeletal maturation. Nissel et al. [37], reporting the results of the Pfizer International Growth Database (KIGS) in 2008, analyzed data from a cohort of 240 rhGH-treated patients with CKD, of which 65 had functioning renal allografts. They looked at near-final height (near-FH), defined as a height velocity <1 cm/year, advanced clinical signs of puberty (Tanner Stage 4) in boys with an age of at least 16 years and in girls of at least 14 years of age. They reported a continuous increase in the mean height SDS during rhGH treatment in both boys and girls. In 2008, Bérard et al. [38] reporting for the French Society of Pediatric Nephrology, highlighted the benefits of rhGH treatment, not only for increased growth in the months following initiation of the rhGH but also for the achievement of a better prognosis for adult height. Their findings emphasized the value of early treatment, suggesting that if rhGH treatment were initiated as soon as height SDS was <−2.0, the FH of patients with CKD would become nearly normal.

After 2010, several single-center reports have addressed FH after transplantation in childhood. Gil et al. [39] in Argentina, evaluated 33 patients (27 male, 6 female) aged 13.24 ± 3 years, who had undergone KT and received rhGH treatment for ≥36 months, and compared them to 14 (8 males and 6 females), who did not receive rhGH therapy after receiving a KT (controls). Both groups were followed and assessed when they reached FH. Final height was below the lower quartile in only 37% of boys and 33.3% of girls in the rhGH-treated group compared with 87.5% in boys and 100% of girls in the controls. Final height SDS in the rhGH-treated patients was significantly higher than that in controls. In both groups, a similar reduction in GFR was observed. In 2014, Harambat et al. [1] reported an analysis of results from the ESPN/ERA-EDTA Registry on a total of 1612 patients from 20 European countries who started RRT before 19 years of age and who had reached FH between 1990 and 2011. In this report, 55% of patients attained an adult height within the normal range. Adjusted for age at the start of RRT and primary renal diseases, FH increased significantly over time from a height SDS of −2.06 in children who reached adulthood in 1990–1995 to an SDS of −1.33 among those reaching adulthood in 2006–2011. Older age at start of RRT, more recent period of start of RRT, longer time with a functioning graft, and greater height SDS at initiation of RRT were independently associated with a higher FH SDS.

5 Timing of Initiation of rhGH Treatment

The question of the timing of initiation of rhGH treatment in children with growth retardation associated with CKD has been debated since its implementation for this indication. It has been demonstrated, that the growth spurt in the first 2–3 years of life contributes significantly to final adult height [40, 41]. In the 2-year multicenter, randomized, placebo-controlled, double-blind Phase III study of the use of rhGH performed in 1988–1990, 30 of the 125 (24%) participants eligible for inclusion in the study (with a height SDS <−1.88), were <2.5 years of age at enrollment. The treatment and placebo arms of the study were matched for age at randomization [29]. At the completion of this study, the placebo arm subjects were offered rhGH treatment and the treated arm subjects could choose to remain on the rhGH for as long as needed. Twenty of the patients enrolled in the treatment arm continued rhGH treatment for at least 5 years. The maximal growth velocity occurred during the first year of the extended rhGH treatment; however, there was a sustained continued improvement in the height SDS during the succeeding 4 years [42]. Despite a significant growth acceleration in the subjects who previously were in the placebo arm after 1 year of receiving rhGH injections, there was no catch-up growth with the previously rhGH-treated subjects who continued to receive the growth hormone injections. Onset of puberty in children with CKD is delayed by 2–2.5 years and the duration of the pubertal growth spurt is shortened by 1 year, contributing to the impairment of the pubertal growth spurt in adolescents with CKD [43]. Studies, which included rhGH treatment in prepubertal and later pubertal stages, have shown that age at treatment initiation is directly related to final adult height, that is, the height gain is better the earlier the rhGH is initiated [44, 45].

6 Recommendations

In 2019, the ESPN, CKD–mineral and bone disorder (MBD), dialysis, and transplantation working groups, with input from an external advisory group of pediatric endocrinologists, pediatric nephrologists, pharmacy, epidemiology, and patient representatives, presented clinical practice recommendations (CPRs) for the use of rhGH in children with CKD, those treated with dialysis, and after renal transplantation [46]. With the caveat that when suitable evidence was lacking, some of the recommendations were based on expert opinion, they recommended that children with growth potential who are in Stage 3–5 CKD or on dialysis should be candidates for rhGH therapy. This was conditional on them having persistent growth failure, defined as a height below the 3rd percentile for age and sex and a height velocity below the 25th percentile, and once other potentially treatable risk factors for growth failure have been adequately addressed. Genetic syndromes associated with CKD, severe secondary hyperparathyroidism, severe diabetic retinopathy, active malignancy, and acute critical illnesses were cited as contraindications to the use of rhGH. In children who have received a KT and fulfill the above growth criteria, they recommended initiation of rhGH therapy 1 year after transplantation if spontaneous catch-up growth does not occur and steroid-free immunosuppression is not a feasible option [46]. In 2013, in an editorial on the meta-analysis by Wu et al. [35], Mehls and Fine [47], who in the 1980s, initiated the research on the use of rhGH for the treatment of children with CKD-associated growth retardation, commented that despite the available data on its efficacy and safety in short children with CKD before and after KT, rhGH is not used in the majority of short children prior to and after transplantation. They recommended that in these patients, early individual decisions for or against rhGH treatment should be made as soon as other treatment strategies, such as steroid withdrawal, have failed or are not indicated. These authors expressed their belief that decisions for rhGH treatment at a later pubertal age come too late for a significant growth response and/or improvement of FH.

7 Underutilization and Challenges to rhGH Treatment

Since the advent of rhGH treatment of children with severely stunted growth associated with CKD, a plethora of data showing significantly improved growth and FH in rhGH-treated children, both during CKD and posttransplantation, have been published [1, 19, 21-34]. However, despite its documented effectiveness, this treatment has been underutilized. A NAPRTCS annual report 20 years after the phase I studies of rhGH use in children with CKD were conducted reported that at enrollment only 11.1% of patients with a height SDS worse than −1.88 were being treated with rhGH, increasing only to 22.1% 12 months after enrollment [48]. More recently, data from the chronic kidney disease in children (CKiD) study showed that 77% of children with height SDS <−1.88 enrolled were not prescribed rhGH [49], and a survey of seven pediatric nephrology centers in the Midwest Pediatric Nephrology Consortium conducted in 2017, revealed that 51% of severely growth-retarded children with CKD had not received rhGH [50]. In 2020, members of the Italian Societies of Pediatric Nephrology and Pediatric Endocrinology surveyed 15 pediatric nephrologists and 17 pediatric endocrinologists involved in the care of CKD patients with growth retardation, from centers across Italy, to establish the level of adherence to the ESPN generated PCRs [51]. In regard to age at which rhGH treatment should be initiated, the majority of the experts from both specialties surveyed agreed it is necessary to start rhGH therapy in patients both younger than 2 years of age with a height 2 SD below the mean, and in children with CKD and growth failure older than 2 years when height falls below the 3rd percentile. As to the question regarding kidney function and initiation of rhGH treatment, 42% of specialists thought initiation of rhGH treatment is indicated at an eGFR <60 mL/min/1.73 m², whereas 26% of the two specialties' experts thought rhGH treatment should be started when eGFR is ≤75 mL/min/1.73 m². However, 30% of the pediatric endocrinologist thought that rhGH treatment should only be started at an eGFR <30 mL/min/1.73 m², leading the authors to emphasize the importance of closer cooperation and exchange of information within the multidisciplinary team involved in the care of growth failure of pediatric CKD patients [51]. Efforts have been made by several groups to determine the obstacles and challenges to better utilization of this important added therapy in these patients. The most commonly cited factors as obstacles preventing children with CKD from receiving rhGH from both patients and physicians are: hesitation to submit to daily injections especially when a KT is imminent, family refusal, nonadherence, barriers encountered in obtaining insurance coverage for the rhGH, increased parathyroid hormone levels, and lack of clear guidelines for physicians. However, no explanation was apparent for 25% of the short children with CKD [52, 53].

8 Conclusions

Growth retardation and short FH is a significant complication of CKD beginning in childhood. Despite adequate treatments of the acidemia, providing adequate nutrition, treating and preventing bone and mineral disorders, and correcting other factors associated with growth failure in children with CKD, a high percentage of patients reach RRT initiation >2 SD below the mean and do not demonstrate catch-up growth post-KT, therefore ending with an FH below their genetic potential. rhGH was introduced as a treatment for the short stature associated with CKD beginning in childhood in the late 1980s–early 1990s, after initial studies showed increased growth velocity and improved length and height SDS in animal and human uremic subjects. Over the more than three decades since, multiple studies in different CKD stages, in ESKD and post-KT have been conducted, with data showing significantly improved growth and FH in rhGH-treated patients. In addition, studies have demonstrated that better height outcomes are achieved the earlier rhGH treatment is initiated. Potential adverse effects have also been studied in the earlier shorter trials, as well as in trials with long-term treatment. These studies revealed no significant acceleration in bone maturation over CA or perturbations in bone biology or anatomy, no faster progression of CKD, no increased incidence of diabetes mellitus, no increased rejection episodes in KT recipients, and no increase in ICP or malignancies. Additionally, studies showed significant and persistent better graft function up to 10 years after transplantation, in children who were treated with rhGH pre-KT compared with non-rhGH-treated recipients.

Surveys of health-related quality of life reveal a significant improvement in social, emotional, and school functioning in rhGH-treated patients. Adults who had been treated with rhGH and reached a near-normal or normal FH, report improvement in work and relationship success. Clinical practice guidelines have been generated by several societies and working groups recommending rhGH treatment in CKD 3–5, including patients on dialysis and after KT.

Despite these data and the published CPGs, to date, this therapy is underutilized. The main cited barriers to implementation of rhGH in the treatment of the short stature associated with CKD are the need for commitment to daily injections, financial challenges in obtaining coverage for the medication, physicians' unfamiliarity with guidelines for time of treatment initiation, pretreatment work-up and follow-up of rhGH-treated patients, and fear of AEs by patients, their families and their physicians. More judicious utilization of this successful treatment of a serious complication of childhood CKD will require more emphasis to be placed on educating patients, their caregivers, and all members of the multidisciplinary treating team. Additional studies are needed to assess the longer term rhGH treatment in larger cohorts of patients, leading to generation of more supportive data and clearer recommendations.

Although rhGH is the only therapeutic agent targeting the GH/IGF axis approved for the treatment of short stature in pediatric patients with CKD, recombinant IGF-I (rhIGF-I) has been proposed as a potentially beneficial option for these patients [54], and although combination therapy with rhGH and rhIGF-I to date has only been studied in animal models, it has also been suggested as a future therapeutic consideration in treatment of CKD-associated short stature [55].

Disclosure

The author has nothing to report.