Abstract
Introduction: Growth retardation is common in children with chronic kidney disease (CKD) and reflects CKD severity. Recombinant human growth hormone (rhGH) treatment was approved for CKD in 1995. We describe treatment patterns and growth outcomes in children with congenital CKD in three pediatric nephrology departments. Methods: We included patients with kidney transplantation performed between 2015 and 2020 at an age of 3–18 years. Data were collected at four timepoints: CKD diagnosis, initiation of rhGH, initiation of dialysis, and transplantation. Results: Among 87 patients, 42 (48%) received rhGH. The median height at treatment initiation was −2.0 SDS, with a median height gain of +0.7 SD (p < 0.0001) in 1.7 years. Growth outcomes were negatively associated with older age and CKD stage 5. The 45 rhGH-untreated patients lost 0.6 SD (p = 0.02) from diagnosis to transplantation but maintained their height in the normal range. At transplantation, 26% of rhGH-treated and 9% of rhGH-untreated patients had a height SDS below −2 SDS. rhGH was initiated by nephrologists in 52% of cases and endocrinologists in 48%. Deviations from marketing authorization criteria were observed in 68% of cases: endocrinologists typically prescribed rhGH for children under 2 years, while nephrologists prescribed it for patients with a height above −2 SDS. Conclusion: About half of CKD patients received rhGH treatment, resulting in significant height gain. Untreated patients were not adversely affected in terms of height. These data highlight the importance of careful monitoring of growth and rhGH treatment if needed in patients with CKD.
Introduction
Growth is an important therapeutic challenge for children suffering from chronic kidney disease (CKD) [1]. In 2019, 36% of children with CKD experienced growth failure with a height <−1.9 SDS [2], particularly in cases with congenital CKD [3, 4]. Furthermore, children with growth failure at the time of transplantation have 49% shorter graft survival time until glomerular filtration rate (GFR) drops below 45 mL/min/1.73 m2 compared to those with normal height [5]. Several factors influence the severity of growth failure: congenital disease versus acquired disease [3, 6], younger age at CKD diagnosis [3, 7, 8], and lower GFR [2, 8].
Growth failure in CKD is multifactorial. Malnutrition, hyperparathyroidism, acidosis, and anemia are associated with CKD and impair statural growth. The somatotropic axis is also affected, contributing to CKD-related growth failure due to resistance to growth hormone [2, 3, 9, 10] primarily because of increased levels of inhibitory insulin-like growth factor-binding protein, which reduces IGF1 bioavailability.
Over the past 30 years, nephrological, nutritional, and endocrinological therapies for children with CKD have increased their adult height. In the American NAPRTCS cohort [11], mean adult height increased from −2.1 SDS in 1990–1995 to −1.3 SDS in 2006–2011 [12], and mean height at kidney transplant increased from −2.4 SDS in 1987 to −1.4 SDS in 2005.
Several clinical studies have shown the effectiveness of recombinant human growth hormone (rhGH) treatment in children with CKD [13]. Haffner et al. [14] reported that adult height of treated patients was −1.6 SDS versus −2.1 SDS in untreated patients. Sixty-five percent of treated patients achieved a normal adult height ≥−2 SDS [14]. Factors positively associated with therapeutic response included height at the start of rhGH treatment [15], deviation from parental target height [14‒16], treatment duration [14, 15], initiation of rhGH before puberty [15], duration of rhGH treatment under conservative CKD therapy (before dialysis) [15, 17, 18], and male sex [14, 15].
Approval for rhGH treatment in children with CKD was granted in 1995. Criteria used in France for initiating rhGH in CKD include height ≤−2 SDS or growth velocity <2 cm/year, age >2 years, GFR <60 mL/min/1.73 m2, bone age <11 years in girls and <13 years in boys, nephrological management of CKD for at least 1 year, and no active malignancy. The recommended dose of rhGH is 0.045–0.050 mg/kg/day, and rhGH treatment should be stopped at kidney transplantation (KT).
Since then, according to these criteria, rhGH treatment has been initiated and monitored in CKD patients until KT, either by pediatric nephrologists, endocrinologists, or both. The aim of the study was to report contemporary results of growth management in children with CKD in 3 pediatric nephrology units in Paris and address several questions: how many patients need to be treated with rhGH? Who initiates and follows up patients during treatment? What results are achieved? How do untreated patients grow until KT?
Methods
Study Population
Children who received a first KT between January 1, 2015 and December 31, 2020, in three pediatric academic centers in Paris, France (Armand-Trousseau, Necker-Enfants-Malades, and Robert-Debré hospitals) were eligible for inclusion. We included patients with congenital CKD who had a chronological age of 3–18 years at the time of transplantation. Exclusion criteria included cystinosis, specific syndromes, or comorbidities associated with abnormal growth (such as methylmalonic acidemia, Schimke syndrome, Fanconi anemia), previous organ or kidney transplantation, KT occurring less than 1 year after the diagnosis of kidney disease.
Data were collected from medical records covering the period from diagnosis of kidney disease until KT. Included patients were classified into two groups based on whether they received rhGH therapy prior to KT.
Collected Variables
The primary diagnosis of the congenital disease was documented for each patient. For cases of antenatal diagnosis of CKD, the age at diagnosis was considered to be the date of birth. Four key timepoints were analyzed: diagnosis of kidney disease, initiation of rhGH therapy (if applicable), initiation of dialysis (peritoneal or hemodialysis if applicable), and KT. At each timepoint chronological age, height, weight, and pubertal stage according to Tanner were recorded. Growth retardation was defined as height SDS <−2. Parental heights were collected to calculate target height (mean parental height plus or minus 6.5 cm for boys and girls, respectively). Target height, height, and weight were expressed as SDS according to the French population references [19]. Corrected height for target height was calculated as (patient’s height SDS – target height SDS) and was considered as normal between −1.5 SD and +1.5 SD. At the initiation of rhGH, the following data were collected: whether the prescriber was an endocrinologist or a nephrologist, the prescribed dose in mg/day and in mg/kg/d, the calculated GFR according to the modified Schwartz formula [20] {(36.5 × height [cm])/serum creatinine (µmol/L)} and the pre-therapeutic biological assessment. rhGH therapy prescriptions were analyzed according to French marketing authorization criteria. Auxological parameters, pubertal stage, and rhGH dose were yearly collected until KT.
Statistical Analysis
Results are expressed as median (interquartile range) or frequencies (n, %). Comparison tests between treated and untreated subjects were performed using methods suited to the type and distribution of the variables: χ2 or Fisher’s test for categorical variables; Student’s t test, or Wilcoxon-Mann-Whitney test for continuous variables. The significance threshold was set at 0.05, and all the tests were two-tailed.
To investigate the factors associated with therapeutic response, a favorable growth outcome was defined as a difference between height SDS at rhGH start and height SDS at KT ≥0. A generalized logistic regression model was applied with the following criteria at rhGH initiation: age, gender, Tanner stage <2, height (SDS), corrected height for target height <−1.5 SDS, and dialysis. These parameters were adjusted for rhGH treatment duration and were incorporated into the multivariate model when significant at the 0.20 univariate threshold and with an exit threshold at 0.05. All statistical analyses were performed using SAS for Windows v9.4, (c) 2016 by SAS Institute Inc., Cary, NC, USA.
Results
One hundred and twenty-five patients with congenital CKD underwent KT between 3 and 18 years of age during the study period (Fig. 1). Thirty-height patients were excluded. Diseases associated with growth abnormalities leading to exclusion included methylmalonic acidemia (n = 11), Schimke syndrome (n = 4), mitochondrial cytopathy (n = 1), Saldino-Mainzer syndrome (n = 1), Alagille syndrome (n = 1), Hirschsprung’s disease (n = 1), Fanconi anemia (n = 1), severe combined immunodeficiency (n = 1), and congenital adrenal hyperplasia (n = 1). Eighty-seven patients were included, among whom 42 (48%) were treated with rhGH before KT (Fig. 1). The chronological age at diagnosis was similar between the two groups (1.0 year vs. 2.1 years, p = 0.10), as was the percentage of dialyzed patients in each group (88.1% vs. 75.6%, p = 0.13) (Table 1). rhGH-treated patients were younger at initiation of dialysis (6.9 vs. 12.8 years, p = 0.003) and at transplantation (9.5 vs. 14.9 years, p < 0.001). The proportion of rhGH-treated patients and the distribution of CKD etiologies were similar across the three centers.
Clinical characteristics of the two groups of patients
. | rhGH group, N = 42 . | Non-rhGH group, N = 45 . | p value . |
---|---|---|---|
Males, N (%) | 25 (59.5) | 30 (66.7) | |
Primary kidney disease, N (%) | |||
CAKUT | 18 (42.9) | 21 (46.7) | |
Glomerular disease | 12 (28.6) | 17 (37.8) | |
Tubular disease | 12 (28.6) | 6 (13.3) | |
Age at diagnosis, years1,2 | 1.0 [0.0; 5.6] | 2.1 [0.2; 11.9] | 0.10 |
Age at transplantation, years2 | 9.5 [5.6; 13.9] | 14.9 [11.5; 16.3] | <0.001 |
Duration of follow-up, years1,2 | 5.4 [3.3; 8.5] | 7.5 [2.8; 11.5] | 0.44 |
Enteral feeding, N (%) | 11 (26.2) | 8 (18.0) | 0.34 |
Dialysis, N (%) | 37 (88.1) | 34 (75.6) | 0.13 |
Hemodialysis | 23 (54.8) | 24 (53.3) | |
Peritoneal dialysis | 7 (16.7) | 7 (15.6) | |
Both modes | 7 (16.7) | 3 (6.7) | |
Age at dialysis initiation, years2 | 6.9 [3.9; 11.6] | 12.8 [8.6; 14.4] | 0.003 |
Duration of dialysis, years2 | 1.8 [1.0; 2.8] | 1.4 [0.9; 1.9] | 0.07 |
Height at diagnosis (SDS)2 | −1.26 [−1.93; +0.21] | +0.22 [−0.62; +0.78] | 0.03 |
Target height (SDS)2 | −0.09 [−0.34; +0.39] | +0.30 [−0.61; +0.91] | 0.38 |
. | rhGH group, N = 42 . | Non-rhGH group, N = 45 . | p value . |
---|---|---|---|
Males, N (%) | 25 (59.5) | 30 (66.7) | |
Primary kidney disease, N (%) | |||
CAKUT | 18 (42.9) | 21 (46.7) | |
Glomerular disease | 12 (28.6) | 17 (37.8) | |
Tubular disease | 12 (28.6) | 6 (13.3) | |
Age at diagnosis, years1,2 | 1.0 [0.0; 5.6] | 2.1 [0.2; 11.9] | 0.10 |
Age at transplantation, years2 | 9.5 [5.6; 13.9] | 14.9 [11.5; 16.3] | <0.001 |
Duration of follow-up, years1,2 | 5.4 [3.3; 8.5] | 7.5 [2.8; 11.5] | 0.44 |
Enteral feeding, N (%) | 11 (26.2) | 8 (18.0) | 0.34 |
Dialysis, N (%) | 37 (88.1) | 34 (75.6) | 0.13 |
Hemodialysis | 23 (54.8) | 24 (53.3) | |
Peritoneal dialysis | 7 (16.7) | 7 (15.6) | |
Both modes | 7 (16.7) | 3 (6.7) | |
Age at dialysis initiation, years2 | 6.9 [3.9; 11.6] | 12.8 [8.6; 14.4] | 0.003 |
Duration of dialysis, years2 | 1.8 [1.0; 2.8] | 1.4 [0.9; 1.9] | 0.07 |
Height at diagnosis (SDS)2 | −1.26 [−1.93; +0.21] | +0.22 [−0.62; +0.78] | 0.03 |
Target height (SDS)2 | −0.09 [−0.34; +0.39] | +0.30 [−0.61; +0.91] | 0.38 |
CAKUT, congenital anomalies of the kidney and urinary tract; SDS, Standard Deviation Score.
1Antenatal diagnosis is expressed at the birthdate.
2Median [IQR].
Growth in rhGH-Treated Patients
At the initiation of rhGH therapy, 57% of patients were on dialysis and 43% patients were receiving conservative treatment (median GFR: 19 [13; 28] mL/min/1.73 m2). rhGH therapy was initiated at a median chronological age of 7.4 years [3.4; 10.7], 3.9 years [1.5; 5.4] after the diagnosis of CKD.
During the years preceding the initiation of rhGH treatment, patients experienced a significant loss of height of −0.7 SD [−2.4; −0.3] (p < 0.0001), leading to a median height at the start of rhGH therapy of −2.0 SDS [−2.7; −1.6] (Fig. 2). rhGH treatment was initiated by the nephrologist in charge of the patient in 52% of cases and by an endocrinologist in 48% of cases. The median rhGH dosage was 0.044 [0.035; 0.048] mg/kg/day. Eighty-one percent of patients were prepubertal, and 12% patients were Tanner stage 2. One patient had advanced puberty (Tanner stage 4).
Changes in height SDS during follow-up. rhGH-treated patients in green and non-rhGH-treated patients in red. Median heights are indicated in the boxes. KT, kidney transplantation; rhGH, recombinant human growth hormone; SDS, Standard Deviation Score.
Changes in height SDS during follow-up. rhGH-treated patients in green and non-rhGH-treated patients in red. Median heights are indicated in the boxes. KT, kidney transplantation; rhGH, recombinant human growth hormone; SDS, Standard Deviation Score.
Over 1.7 years [1.0; 3.1] of treatment, the median height gain was + 0.7 SD [+0.2; +1.1] (p < 0.001) which corresponds to +0.4 SD per year. The median height SDS at KT was −1.5 SDS [−2.1; −0.8] (Fig. 2). The prevalence of growth retardation decreased from 48% at the start of treatment to 26% at KT. In the 30 patients with available target height data, the corrected height for target height SDS was in the normal range for 60% of patients at KT. The median height gain was +0.5 SD per year [+0.2; +0.8] of treatment in patients under conservative treatment, compared to +0.3 SD per year [−0.1; +0.6] in dialyzed patients.
Factors Associated with Growth Outcome
Growth outcome was favorable in 76% of patients. The chronological age at rhGH initiation was negatively associated with growth response: each 1-year increase in age at rhGH initiation was associated with a 22% decrease in catch-up growth (p = 0.04; OR 0.78; 95% CI [0.62–0.99]). Starting rhGH therapy during dialysis was also negatively associated with catch-up growth (p = 0.049; OR 0.01; 95% CI [0.001–0.99]). After adjusting for age at rhGH onset, there was no significant difference in height gain during rhGH therapy whether the prescriber was a nephrologist or an endocrinologist (p = 0.38) (Table 2).
Patient characteristics and rhGH therapy modalities according to the prescriber
. | Nephrologist (n = 22) . | Endocrinologist (n = 20) . | p value1 . |
---|---|---|---|
Age at start of rhGH therapy, years2 | 8.1 [4.8; 9.6] | 5.0 [1.6; 11.2] | 0.25 |
Duration of CKD, years2 | 4.8 [3.3; 8.5] | 1.6 [1.4; 3.2] | 0.006 |
rhGH therapy duration, years2 | 1.7 [1.0; 3.3] | 1.8 [1.3; 3.1] | 0.74 |
Kidney disease management, N (%) | 0.37 | ||
Conservative treatment | 8 (36.4) | 10 (50.0) | |
Dialysis | 14 (63.6) | 10 (50.0) | |
Off-label prescription, N (%) | 12 (55.0) | 15 (75.0) | 0.10 |
Height at rhGH start (SDS)2 | −1.83 [–2.42; −1.51] | −2.22 [−2.73; −1.63] | |
Height at KT (SDS)2 | −1.71 [–2.21; −0.74] | −1.41 [−1.89; −0.75] | |
Delta height KT-rhGH (SD)2 | +0.63 [−0.06; +0.98] | +0.79 [+0.35; +1.14] | 0.38 |
. | Nephrologist (n = 22) . | Endocrinologist (n = 20) . | p value1 . |
---|---|---|---|
Age at start of rhGH therapy, years2 | 8.1 [4.8; 9.6] | 5.0 [1.6; 11.2] | 0.25 |
Duration of CKD, years2 | 4.8 [3.3; 8.5] | 1.6 [1.4; 3.2] | 0.006 |
rhGH therapy duration, years2 | 1.7 [1.0; 3.3] | 1.8 [1.3; 3.1] | 0.74 |
Kidney disease management, N (%) | 0.37 | ||
Conservative treatment | 8 (36.4) | 10 (50.0) | |
Dialysis | 14 (63.6) | 10 (50.0) | |
Off-label prescription, N (%) | 12 (55.0) | 15 (75.0) | 0.10 |
Height at rhGH start (SDS)2 | −1.83 [–2.42; −1.51] | −2.22 [−2.73; −1.63] | |
Height at KT (SDS)2 | −1.71 [–2.21; −0.74] | −1.41 [−1.89; −0.75] | |
Delta height KT-rhGH (SD)2 | +0.63 [−0.06; +0.98] | +0.79 [+0.35; +1.14] | 0.38 |
CKD, chronic kidney disease; KT, kidney transplantation; rhGH, recombinant human growth hormone.
1Wilcoxon-Mann-Whitney test (quantitative) or chi-square test (qualitative).
2Median [Q1; Q3].
Treatment Modalities
rhGH therapy was initiated by the referring pediatric nephrologist in 52% of patients and a pediatric endocrinologist in 48% of patients. Sixty-eight percent of prescriptions deviated from French authorization criteria (Fig. 3a). Endocrinologists tended to initiate rhGH therapy in patients younger than 2 years, while nephrologists prescribed rhGH therapy for less stunted patients (Fig. 3b). As shown in Table 2, when initiated by an endocrinologist, rhGH therapy was started earlier during CKD (1.6 vs. 4.8 years; p = 0.01) and tended to be prescribed more often in patients under conservative treatment of CKD (50% vs. 36%, p = 0.37).
Criteria for off-label prescriptions. a Initial criteria for off-label prescription according to French insurance reimbursement. The total number of criteria exceeds the number of patients (n = 27) because some patients met several criteria. b Initial criteria for off-label prescription according to the first prescriber (pediatric nephrologist or endocrinologist). CKD, chronic kidney disease; GFR, glomerular filtration rate; SDS, Standard Deviation Score.
Criteria for off-label prescriptions. a Initial criteria for off-label prescription according to French insurance reimbursement. The total number of criteria exceeds the number of patients (n = 27) because some patients met several criteria. b Initial criteria for off-label prescription according to the first prescriber (pediatric nephrologist or endocrinologist). CKD, chronic kidney disease; GFR, glomerular filtration rate; SDS, Standard Deviation Score.
At rhGH initiation, IGF1 and PTH levels were measured in 81% of patients (median value: −0.1 SDS [−1.3; +0.8]) and 95% of patients (median value 7.6 pmol/L [3.4; 17.3]), respectively. Three patients suffered from severe hyperparathyroidism defined as PTH >53 pmol/L (values: 67.2; 62.0 and 53.3 pmol/L).
During follow-up, the median rhGH dosage was 0.036 [0.033; 0.045] mg/kg/d. Serum IGF1 levels were monitored in all patients, with a median of 4 [2, 6] samples per patient. Decreases in rhGH dose were linked to a lack of adjustment for weight gain in 52% of cases and to high serum IGF1 levels (>+2 SDS) in 27% of cases. Increases in rhGH dosage were linked to patients’ decrease of height SDS, the onset of puberty, or worsening GFR.
rhGH therapy was interrupted before KT in 17% of patients. Treatment was discontinued in 3 patients for the following reasons: attainment of adult height, severe hyperparathyroidism (PTH: 102 pmol/L), and patient decision. Treatment was temporarily interrupted in 4 cases due to hyperparathyroidism, preventive bilateral nephrectomy in Denys-Drash syndrome, return to the target height channel (+1 SDS) with advanced bone maturation, and headaches (without intracranial hypertension on brain imaging).
In the rhGH-treated group, no data on pubertal development were available for 12% (n = 5) of patients, and parental target height was missing for 26% (n = 11) patients. In the untreated group, no data of pubertal development were available for 38% of patients (n = 17), and parental target height was missing for 51% of patients.
Growth in Non-rhGH-Treated Patients
Fifty-two percent of patients did not receive rhGH treatment. Figure 2 shows that height SDS was significantly different between the two groups at each follow-up time point. From diagnosis to KT, untreated patients experienced a median loss of height of −0.6 DS [−1.6; +0.3] (p = 0.02) (Fig. 2). Their median height SDS at KT was −0.4 SD [−1.1; +0.4]. Eighteen percent of patients had a height SDS <−2 during their follow-up, and half of them had height SDS <−2 at KT. These patients did not receive rhGH therapy for the following reasons: spontaneous catch-up, active cancer, near final height, or unknown reason (n = 2).
Discussion
This study represents the first French multicentric cohort study since the approval for rhGH treatment in CKD in 1995. It provides an overview of current practices regarding the monitoring of growth and rhGH treatment in patients followed at three pediatric nephrology centers. In this cohort, 48% of patients received rhGH treatment prior to KT. rhGH therapy effectively increased height growth, as 74% of patients had a height > −2 SDS at KT, while most of rhGH-untreated patients (91%) achieved a height >−2 SDS at KT. The prevalence of rhGH treatment was similar to the French national transplantation record, with 44% of patients undergoing dialysis before the age of 20 years old, receiving rhGH therapy [21].
With rhGH, the median height gain was +0.7 SD over 1.7 years of treatment which is slightly lower than the height gains reported in previously published studies. In 1994, Fine et al. [22] reported a height gain of +1.4 SD over 2 years of treatment. Haffner et al. [23], similarly reported a height gain of +1.3 SD over 2 years of treatment in 1998. Several factors in our cohort may explain this lower height gain. First, these patients were less severely stunted than those included in earlier clinical studies, where heights ranged from −3 to −2 SDS [22, 24]. Second, as discussed further, the modalities of treatment were not optimal. At the initiation of rhGH therapy, 51% of patients were in CKD stage 5 requiring dialysis, a condition known to be unfavorable for growth. In children with CKD, the prevalence of growth retardation is inversely related to the level of glomerular filtration [2, 3], and the height gain during rhGH therapy is significantly greater in children receiving conservative treatment than in those on dialysis (+1.1 SD vs. + 0.5 SD) [25]. Conservative treatment is not only an independent factor associated with short-term growth response but also with adult height [15, 23]. Thus, initiating rhGH therapy early in the course of CKD, before severe growth retardation due to decreased GFR occurs, is crucial for optimal rhGH efficacy. The late initiation of rhGH treatment in these patients resulted in a short duration of therapy before KT, with one-third of our patients treated for less than 1 year. The duration of treatment until KT is also known to be a predictive factor of growth response [15, 23]. Additionally, rhGH doses administered to the patients were not accurately adjusted during follow-up. Due to growth hormone resistance, a high dose of 0.045–0.050 mg/kg/day is currently recommended for growth-retarded CKD patients [26]. In this study, the starting rhGH dose of 0.044 mg/kg/day was consistent with recommendations but decreased to 0.036 mg/kg/day during follow-up. This decrease resulted from inappropriate dose adjustments with patient’s weight and elevated plasma IGF1 levels. Interpreting serum IGF1 levels in CKD is challenging, as assays measure total circulating IGF1, including both active free IGF1 and IGF1 bound to insulin-like growth factor-binding protein and ALS proteins, which accumulate as GFR declines. This explains high IGF1 levels in end-stage kidney disease, regardless of rhGH treatment. Thus, measuring IGF1 is not recommended for monitoring rhGH treatment in CKD patients [27]. Instead, growth velocity is the best criterion for assessing the efficacy and adherence to rhGH therapy. Third, adherence to treatment in these patients, who receive many other medications, is difficult to evaluate. Akchurin et al. [28] demonstrated that adherence to rhGH therapy was associated with a significantly higher height gain of +0.2 SD/year compared to non-adherent CKD patients. Therefore, it cannot be ruled out that the lower height gain reported in this study may partly result from lower compliance to treatment in routine care compared to clinical trials.
Sixty-eight percent of prescriptions deviated from the criteria for rhGH use in France. These deviations mainly concerned height SDS, age, and duration of follow-up of CKD patients at initiation. However, based on many years of clinical practice since the approval, new recommendations for rhGH treatment in CKD patients were published in 2006 in the USA [11] and more recently in 2019 in Europe [27]. For instance, the European consensus recommends initiating rhGH therapy in patients whose height is between the 3rd and 10th percentile and growth velocity <25th percentile. Moreover, in patients whose height is >−2 SDS, the distance from target height channel is discussed as a potential criterion for initiating rhGH therapy [27, 29]. Regarding the age at initiation, Drube et al. [27] suggest starting rhGH therapy at the age of 6 months, in association with nutritional management when growth rate is reduced. This recommendation is supported by the severe impact of chronic disease on growth during the first years of life [3, 30] and the larger catch-up of growth in young children [23, 31, 32].
The question of whether rhGH treatment should be monitored by a pediatric endocrinologist or by a pediatric nephrologist is still debated and mostly depends on local resources and practices. In our study, nearly all patients were managed by a nephrologist at 2 centers, while most patients were followed by an endocrinologist at the third center. These differences result from working habits of medical teams and local availability of pediatric endocrinologists for the follow-up of CKD patients. We identified differences in practice between pediatric nephrologists and endocrinologists, with the latter more likely to initiate treatment in younger patients and fewer missing data on target height and pubertal stage in patients’ charts. In a study performed in the USA, 27% of patients were referred to a pediatric endocrinologist before starting rhGH therapy, with significant variability based on the availability of specialists [33]. In smaller centers with fewer than 5 pediatric nephrologists, 44% of patients were followed by an endocrinologist, compared to larger centers where 6% of patients were followed by an endocrinologist [33]. In any case, it is recommended by several consensus statements to refer patients to an endocrinologist in cases of delayed puberty or insufficient catch-up growth during rhGH therapy [11, 27]. Furthermore, the inappropriate adjustments of rhGH doses noted in this study, which may have reduced treatment efficacy, underscore the need for collaboration with endocrinologists during the follow-up.
Fifty-two percent of patients did not receive rhGH therapy during the study period. Although they experienced a significant loss of height SDS throughout their disease until KT, the impact of CKD on growth was less severe. These patients were significantly taller than the treated patients at diagnosis, dialysis, and KT and possibly indicating less severe disease, as suggested by their older age at the dialysis initiation. Only 4 patients had a height <−2 SDS at KT, reflecting the medical commitment to manage growth retardation.
This study has several limitations. Data were collected retrospectively, resulting in several missing data, especially regarding target height and pubertal assessment. Factors such as anemia, acidosis, and hyperparathyroidism, which could influence growth response to rhGH therapy, were not recorded. The number of included patients was relatively small, reducing the power of statistical analysis and rendering subgroup analyses inappropriate. Lastly, this multicentric study, which included 3 university hospitals in Paris, may not reflect other practices [33].
In conclusion, monitoring of growth in CKD patients was satisfactory across the three centers involved in this study. During the study period, no patient missed the opportunity to receive rhGH therapy. In stunted CKD patients, rhGH therapy was effective, as most had a height within the normal range at KT. However, a better collaboration between nephrologists and endocrinologists is needed to improve the monitoring of rhGH therapy, particularly in terms of initiation timing, dose adjustments and pubertal follow-up.
Statement of Ethics
This study protocol was reviewed and approved by the Local Ethics Committee, Robert-Debré Hospital, Paris, France (Approval No. 2021-561bis), in accordance with the Declaration of Helsinki. The patients and their parents did not object to the collection of their data. Written informed consent from the parent/legal guardian of participants was not required for this retrospective study in accordance with local guidelines.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Both S.D. and D.S. made substantial contribution to the study design. Data collection and management were performed by S.D.. C.D., R.S., and T.U. contributed to data collection by providing cohort patients for each center. Data analysis was performed by S.D. and P.B.. Data interpretation was completed by D.S. and J.-C.C.. S.D. and D.S. provided the initial draft of the manuscript. C.D., R.S., J.-C.C., and T.U. contributed to the final version of the manuscript.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.