Kidney growth and renal functions under the growth hormone replacement therapy in children

Abstract

Objective: The aim of this study was to investigate the kidney growth and renal functions in children receiving recombinant human growth hormone (rhGH) treatment. Materials and methods: A total of 37 children who received rhGH for 1.5 years before the study was started and 48 healthy controls were included at first evaluation. Hormone levels were determined and kidney sizes were measured by ultrasound. Kidney functions were assessed by serum creatinine and estimated glomerular filtration rate (eGFR). After 3 years of first evaluation, 23 patients were re-assessed. Results: Kidney sizes were found to be lower in rhGH received children compared with controls at first evaluation (p < 0.05). Significant positive correlations were found between anthropometric measurements and kidney length and kidney volume (p < 0.05). Height was the most significant predictor of kidney volume in rhGH received children (p < 0.001). After 3-years of follow-up significantly increases were found in kidney length and volume compared with the first measurements (p < 0.05). Increase percentage of body height was similar to increasing percent of kidney length and liver long axis (14.2%, 11.7.1% and 7.7%, respectively, p > 0.05). Although no abnormal renal function test results were found at first and second evaluations; rhGH received children had significantly lower eGFR, at first evaluation, compared with controls; however, renal functions significantly increased after 3 years of follow-up (p < 0.05). Conclusions: In conclusion, effect rhGH treatment on kidney growth is parallel to growth in body height and other visceral organs. A 3-years rhGH treatment resulted in significant increases in renal functions.

• Children
• growth hormone deficiency
• IGF-1
• renal functions
• renal growth

Introduction

Growth hormone (GH) and insulin-like growth factor-1 (IGF-1), together with other growth factors and cytokines, have important roles in adaptive morphological and functional changes in the kidney, including development, growth and functions of kidney.1 IGF-1 has been found to be associated with renal hypertrophy and compensatory renal growth. Both GH and IGF-1 are growth stimulants for many organs, including kidney.1,2 Treatment with IGF-1 alone induced a significant increase in body length, weight and the weight of kidneys in Snell dwarf mice.2 Animal models of hepatic IGF-1 deficiency showed decreased kidney weight probably due to decreased serum IGF-1 levels since giving systemic IGF-1 has led to increase in kidney size.3 The efficacy and safety of recombinant human growth hormone (rhGH) treatment has been proven in short children with chronic kidney disease who are on conservative treatment or undergone dialysis treatment.4

Although there are some experimental studies5,6 investigated the role of GH deficiency, rhGH, and IGF-1 on renal growth in animals, no clinical data has been reported up to date about the renal growth in rhGH received children. Therefore, in this study, we aimed to investigate the role of rhGH on kidney growth in children who receiving rhGH supplementation for at least 4 years period. According to best of our knowledge, this is the first study dealing with renal growth in children receiving rhGH treatment as a longitudinal prospective manner.

Patients and methods

Patients

The study group included 22 children (13 boys, 9 girls) with isolated GHD (IGHD) and 15 children (12 boys, 3 girls) with multiple pituitary hormone deficiency (MPHD). The patients were already treated with rhGH for nearly 1.5 years before the study was started. All of children with MPHD had complete GHD. Due to different mean ages of these two subgroups, we recruited different control groups for each of the study subgroups. The control group for IGHD was composed of 36 children having the similar mean age (13 years) and gender distribution (24 boys, 12 girls), and control subjects for MPHD included 32 healthy children (25 boys, 7 girls; mean age 9.6 years) (Table 1). However, total number of controls was 48, since 20 healthy children recruited as controls both for IGHD and MPHD groups. Control subjects were selected from the children who were admitted to hospital for routine check-up or routine follow-up examinations and had no clinical or laboratory signs of a systemic illness. The control subjects had normal physical examinations, ultrasonographic findings, blood pressures, serum electrolytes, urea, and creatinine levels. Children, who had anatomical abnormalities that could influence kidney size, including hydronephrosis, vesico-ureteral reflux or renal scars were excluded. Children who were born pre- or post-mature and/or were small or large for gestational age were not included in the control group. Children with hematuria, increased serum urea and creatinine, history of renal surgery, clinical symptoms of dysuria, urinary frequency, enuresis, chronic diseases or urinary tract infections were also excluded.

Table 1. Anthropometric measurements, renal functions and kidney sizes in children with isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD) in comparison with their control subjects at first evaluation.

	IGHD group (n = 22)	Controls (n = 36)	MPHD (n = 15)	Controls (n = 32)	p
Boys/girls	13/9	24/12	12/3	25/7	^aNS; ^bNS
Age, years	13.1 ± 2.2	13.0 ± 2.1	9.4 ± 4.4	9.6 ± 2.9	^aNS; ^bNS
Weight, kg	32.7 ± 11.9	44.6 ± 12.5	22.9 ± 11.5	29.7 ± 11.7	^a0.006; ^b0.053
Height, cm	132 ± 18	151 ± 13	111 ± 22	133 ± 18	^a0.001; ^b0.008
BMI, kg/m^2	17.8 ± 2.8	18.8 ± 3.4	17.2 ± 3.3	17.3 ± 2.9	^aNS; ^bNS
BSA, m^2	1.09 ± 0.27	1.38 ± 0.24	0.82 ± 0.29	1.11 ± 0.30	^a0.002; ^b0.037
Serum creatinine, mg/dL	0.48 ± 0.09	0.52 ± 0.11	0.42 ± 0.09	0.49 ± 0.07	^aNS; ^b0.006
Estimated GFR, mL/min/1.73 m^2	118 ± 21	129 ± 18	113 ± 13.5	127 ± 19	^a0.039; ^b<0.001
Mean Kidney
Length, mm	90.1 ± 13.4	105.1 ± 11.9	79.2 ± 13.4	95.1 ± 12.8	^a<0.001; ^b<0.010
Depth, mm	37.0 ± 6.5	38.4 ± 5.5	34.5 ± 7.2	37.1 ± 4.6	^aNS; ^bNS
Width, mm	46.3 ± 5.6	48.5 ± 5.1	40.2 ± 6.7	44.8 ± 6.2	^aNS; ^b0.025
Kidney volume, cm^3	164.9 ± 52.7	211.9 ± 59.3	118.9 ± 51.2	164.8 ± 66.6	^a0.010; ^b0.013
Liver long axis, mm	199.1 ± 16.7	225.3 ± 12.2	191.0 ± 11.3	209.5 ± 15.3	^a<0.001; ^b<0.001

Notes: BMI, body mass index; BSA, body surface area; GFR, glomerular filtration rate.

^aDifference between IGHD group and its control, ^bDifference between MPHD group and its control.

NS, not significant.

GH deficiency was diagnosed by GH provocation tests. The diagnosis of GHD was made based on the following criteria: (a) Short stature (height below the third percentile values of Turkish children charts),7 (b) decreased growth velocity, (c) delayed skeletal development (bone age under −2SD), and a blunted peak GH response (<10 ng/mL) to two GH provocations tests (L-DOPA and clonidine tests). Priming with sex steroids was done in prepubertal or early pubertal children with bone age >10 years before GH stimulation tests. Fifteen of the IGHD children had complete GHD with peak GH responses less than 5 ng/mL and the remaining had partial GHD with peak GH responses between 5 and 10 ng/mL.

Magnetic resonance imaging (MRI) scans of the IGHD group revealed five cases with pituitary hypoplasia, two pituitary hypoplasia + ectopic posterior pituitary gland + thin infundibulum, two empty cella, one pars intermedia cyst and 12 cases had normal MRI of the pituitary gland. In the MPHD group, there were nine cases with pituitary hypoplasia + ectopic posterior pituitary gland + absence of infundibulum, three cases with pituitary hypoplasia, two with empty sella and one with normal MRI findings.

All patients with MPHD received hormonal replacement therapy. l-thyroxine was administered at a daily dose of 100–125 μg/m². Testosterone enanthate was given at a dose of 25 mg monthly after 14 years of age in boys and ethinyl oestradiol at a daily dose of 2.5 μg after 13 years of age in girls as a replacement for gonadotrophin deficiency. Hydrocortisone was given at a dose of 5–12 mg/m²/day for ACTH deficiency. All patients were treated with subcutaneous injections of rhGH at a dose of 0.1 U/kg per day. Four of the 15 patients with MPHD were administered sex steroid replacement therapy.

The mean GH treatment period before the first evaluation was 20.0 ± 9.7 months for IGHD group and 19.6 ± 9.6 months for MPHD patients. Eleven patients of the 21 with IGHD and 11 of 15 patients with MPHD had completed 18 months of rhGH replacement therapy. The second evaluation was performed after 3 years of rhGH therapy. Twenty-three children with GHD (16 with IGHD, 7 with MPHD) were re-evaluated after 3 years. Renal dimensions were measured at the second time by the same radiologist (Dr. S. E.) and the anthropometric and renal function measurements were performed once again at the same hospital.

Estimated glomerular filtration rate (GFR) was calculated by the new Schwartz formula as GFR (mL/dk/1.73 m²) = 0.413 × height (cm) / Serum creatinine (mg/dL).8

The children were examined and anthropometric measurements were performed by two physicians (Dr. A. E. and Dr. S. Ç.). Anthropometric measurements including body weight and height, and thorough physical examination and urinalysis were recorded on admission. Supine length was measured until the 2 years of age and standing height thereafter, using stadiometer (precision 1 mm) and expressed as standard deviation score (SDS) for chronological age according to reference values of Turkish children.7 Body weight was estimated with a precision of 10 g. All anthropometric measurements were recorded as the mean of three measurements. The body mass index [BMI, weight (kg)/height (m²)] was used as a measure of weight for height. Body surface area (BSA) was determined using the equation as BSA = body weight^0.425× body height^0.725× 0.007184.9

Informed consents were obtained from the parents of children and the study protocol was approved by the Ethical Committee of Dr. Sami Ulus Children’s Hospital.

IGF-1 and IGF binding protein-3 (IGFBP-3) determinations

IGF-1 and IGFBP-3 levels were measured by DSL kits with IRMA coated tube method (Diagnostic Systems Laboratories, Webster, TX). The minimum detection limits for IGF-1 and IGFBP-3 were 0.9 ng/mL and 0.5 ng/mL, respectively. Inter- and intra-assay CVs were 6.9% and 5.1% for IGF-1 and ≤2.3% and 3.8% for IGFBP-3, respectively. GH levels were measured with chemiluminescent immunometric assay by Immulite DPC. The sensitivity of assay was 0.01 ng/mL, and intra- and inter-assay CVs were ≤3.9% and ≤6.1%, respectively.

Thyroid hormones and TSH measurements

Thyroid hormones and thyroid stimulant hormone (TSH) were determined in serum samples shortly after blood sample collections. Thyroid hormones and TSH serum levels were measured by enzyme immunoassay method using commercial kits (Tosoh Corporation, Tokyo, Japan).

Ultrasonography

The LOGIQ 9 ultrasound machine (General Electric Co., Milwaukee, WI) with a 4–10 MHz (General Electronic Co., Milwaukee, WI) was used for ultrasonographic examinations of kidney and liver with an accuracy of 0.1 mm. All the measurements were performed by the same radiologist (Dr. S.E.) at the same device. The probe was placed on the back of the child in a supine position turning right and left sides. The kidney was identified in the sagittal plane along its longitudinal axis. In this position, longitudinal anterior–posterior (ap) measurements of the largest length and width were done. The probe was then rotated 90° and three cross-sectional ap measurements of the width and depth at the hilar level were performed. Mean length, width and depth were calculated as the average of two measurements. For the kidney length measurement, the intra-observer variation was estimated to be 0.30 cm.

Kidney volume was calculated in cubic centimeters using the equation of an ellipsoid: Volume = mean length × mean width × mean depth × 0.523.10 Left and right kidney measurements were added and divided by two for mean kidney dimensions and kidney volumes were added for the combined kidney volume (cm³). The nomograms presented by Luk et al.11 and Leung et al.12 were used for examine whether kidney length and volume of our patients and control subjects were abnormal or not. Renal lengths of the patients were also compared with the normal values derived from an age-based formula proposed by Akhavan et al.13 (length (cm) = age (years) × 0.3 + 6).

Ultrasonographical liver measurements were performed in a supine position. The longitudinal axis of both right and left liver lobes were measured after clear visualization of the liver in the midclavicular plane. Longitudinal axis of right and left liver lobes were added for obtaining liver long axis.

Statistical analysis

Statistical analyses were performed using SPSS 12.0 software package (SPSS, Inc., Chicago, IL). Data were presented as the means plus/minus standard deviations. Statistical differences between the patients and the control groups were evaluated using the Chi-square and Mann–Whitney U tests according to data distribution pattern. Comparison of first and second measurements of the same group was performed by Wilcoxon Signed Ranks test. Pearson’s or Spearman’s correlation analyses and partial correlation analysis were performed to evaluate the relationships between kidney sizes and hormonal/ anthropometric parameters. Multiple regression analysis was performed to detect the most effective factors on kidney dimensions. A p value less than 0.05 was accepted significant.

Results

IGHD subgroup and MPHD subgroups versus controls

The body weight, height and BSA of IGHD and MPHD groups were significantly lower than those of their controls (p < 0.05) (Table 1). The mean age and BMI of both subgroups were similar to those of controls (p > 0.05) (Table 1).

Both subgroup had smaller mean renal length compared with the control group (p < 0.05) (Table 1). However, no significant differences were found in mean depth and width of kidneys between IGHD subgroup and the control subjects (p > 0.05) (Table 1). MPHD subgroup had similar depth but lower kidney width compares to its control group. The mean kidney volume of both subgroup were significantly lower than that of controls (p < 0.05) (Table 1).

In the view point of liver dimensions, both IGHD and MPHD groups had smaller longitudinal axis of liver than that of control groups (p < 0.001) (Table 1).

Comparison of mean kidney sizes of patients with the normal values of nomograms

Comparison of low, normal and high kidney length and total kidney volume according to normal limits of nomograms reported by Luk et al.11 and Leung et al.12 revealed that kidney length by age and by height and kidney volume by age had significantly different distribution patterns between our first and second measurements and control subjects (Table 2). Significantly higher ratios of low kidney sizes were found in patients at first evaluation when compared with controls and with the nomograms (p < 0.05). Significantly different ratios of low, normal and high kidney sizes were found between first and second measurements (p < 0.05) (Table 2).

Table 2. Comparison of low, normal and high kidney sizes in patients and controls using nomograms based on total kidney volume and renal length by age or by height.

	Patients
Nomograms	First evaluation (n = 37)	Second evaluation (n = 23)	Controls (n = 48)	p
Kidney volume by age12
Low	32/37	7/23	8/48	^a<0.001, ^b<0.001
Normal	5/37	12/23	34/48
High	0	4/23	6/48
Kidney length by age13
Low	27/37	5/23	2/48	^a<0.001, ^b<0.001
Normal	10/37	13/23	40/48
High	0	5/23	6/48
Kidney length by height11
Low	4/37	3/23	3/48	^a<0.001, ^b0.002
Normal	33/37	8/23	31/48
High	0	12/23	14/48

Notes: ^aFirst versus second evaluation.

^bFirst evaluation versus controls.

At first evaluation, our patients had significantly lower mean renal length [(right renal length + left renal length)/2] compared with the normal renal length that derived from an age-based formula proposed by Akhavan et al.13 (8.6 ± 1.3 cm vs. 9.5 ± 1.1 cm, p < 0.001). Mean renal length of our control group was comparable to mean normal renal lengths according to this formula13 (9.36 ± 1.32 cm vs. 9.15 ± 1.02 cm, p = 0.07). At second evaluation after 3 years of first evaluation, mean renal length of patients (8.6 ± 1.3 cm vs. 9.6 ± 1.4 cm, p < 0.001) significantly increased.

Renal functions

Although none of our patients had renal insufficiency and all of them had GFR and serum creatinine levels within the normal limits; significantly lower GFR levels were found in children with IGHD/MPHD compared with their control subjects at first evaluation (Table 1). However, no significant differences were found in serum creatinine and GFR values between IGHD and MPHD groups (p > 0.05) (Table 1).

Second evaluation of 23 children after 3 years of first evaluation yielded significantly increased GFR and serum creatinine levels compared with the first evaluation of the same patients (p < 0.001) (Table 2).

Comparisons between first evaluation and after 3 years of follow up

Totally 23 children with GH deficiency completed 3-years follow-up period from starting of the study and were re-evaluated after 4.5 years of rhGH treatment. Significant increases were found in length, depth, width and kidney volumes at second measurement compared with the first evaluation (p < 0.05) (Table 3). Significantly increased liver long axis was also observed at second evaluation (p < 0.001) (Table 3).

Table 3. Comparison of renal functions and visceral organ growth in 23 children with growth hormone deficiency between first evaluation and after 4-years follow-up period (mean ± standard deviation).

	First measurement (n = 23)	Second measurement after 3 years (n = 23)	^ap
Serum creatinine, mg/dL	0.47 ± 0.08	0.59 ± 0.15	0.002
Estimated GFR, mL/min/1.73 m^2	94 ± 7	109 ± 25	0.008
Body height, cm	125.3 ± 19.2	143.5 ± 20.3	0.001
Mean kidney
Length, mm	85.6 ± 13.1	95.7 ± 13.6	0.014
Depth, mm	35.1 ± 6.3	40.5 ± 4.2	0.001
Width, mm	43.6 ± 5.5	48.1 ± 6.6	0.016
Kidney volume, cm^3	139.3 ± 48.1	200.0 ± 59.7	<0.001
Kidney Volume/BSA, cm^3/m^2	143 ± 26	173 ± 37	0.007
Liver long axis, mm	195.4 ± 10.8	210.7 ± 12.4	<0.001

Note: ^aBy Wilcoxon test for paired-samples, NS: Not significant.

The changing percentage of body height (14.2%) was similar to increasing percent of kidney length (11.7%) and liver long axis (7.7%) (p > 0.05). At second evaluation, patients had significantly higher kidney volume/BSA values compared with the first evaluation of before 3 years (p = 0.007) (Table 3).

Correlations

Age and anthropometric measurements including body height, weight and BSA were found to be significantly correlated with kidney length and total kidney volume in total study group (n = 37) including IGHD and MPHD patients (p < 0.05) (data not shown). At first evaluation, IGF-1 and IGFBP-3 had significant positive correlations with kidney length and total kidney volume (p < 0.05) (data not shown). There were also significant positive correlations between the liver long axis and height, weight and BSA (p < 0.05). Liver dimensions had significant positive correlations with serum IGF-1 levels (p < 0.05) (data not shown).

Since age was found to be significantly correlated with nearly all of kidney parameters, we performed partial correlation analysis excluding the effect of age on these parameters at first evaluation (Table 4). After excluding the effect of age, significant positive correlations were persisted between anthropometric variables (height, weight and BSA) and length of both kidneys and kidney volume (p < 0.05 for each pairs). There were also weak positive correlations between IGF-1 and both kidney lengths after adjustment for age (p < 0.05). However, no significant correlations were found between IGFBP3 and kidney length or total kidney volume after age adjustment (p > 0.05) (Table 4).

Table 4. Partial correlation coefficients (r) between hormonal parameters and visceral organ measurements at first evaluation, after adjustment for age in children with growth hormone deficiency (n = 37).

	Left kidney length	Right kidney length	Total kidney volume	Liver right lobe	Liver left lobe
Height	0.774***	0.816***	0.776***	0.599**	0.611***
Weight	0.592**	0.600***	0.708***	0.566**	0.861***
BSA	0.689***	0.712***	0.768***	0.611***	0.927***
IGF-1	0.452*	0.445*	0.218	0.299	0.642**
IGFBP-3	0.162	0.242	0.027	0.048	0.054

Notes: BSA, body surface area; GH, growth hormone.

*p < 0.05; **p < 0.01; ***p < 0.001.

After 3 years of rhGH replacement in 23 children who were re-assessed, significant correlation was found between age and kidney volume (r = 0.497, p = 0.026). Partial correlation analysis at second evaluation, following correction for age, revealed significant correlations of kidney volume with height (r = 0.620, p = 0.005), BSA (r = 0.588, p = 0.008) and weight (r = 475, p = 0.040). Multiple regression analysis revealed that height was the most significant predictor of kidney volume in children with GH deficiency (β = 0.910, p < 0.001). Significant relationship was found between height and kidney length with multiple regression analysis (β = 1.346, p < 0.001).

Discussion

The GH/IGF/IGFBP system comprises the receptors for GH and IGF-1 and insulin-like growth factors (IGFBPs). GH and IGF-1 have important effects on kidney growth, structure and function.14 Although the effects of GH deficiency and administration of GH, IGF-1 or IGFBPs have been investigated in animal studies 1–3,15,16, we found no clinical study about visceral organ growth in humans with GH deficiency by a literature search.

The effects of exogenous rhGH on renal growth in rats have been investigated by Mehls et al. 5 In their experimental study, rhGH has stimulated body growth as well as renal growth, whereas IGF-1 increased renal mass more selectively.5 Obese children have also significantly larger kidneys compared with their normal-weight controls.16

In present study, we investigated the kidney growth of children while receiving rhGH as a first time in the literature, since it has not been investigated previously in humans. Kidney dimensions were measured by ultrasound and kidney volumes were calculated. Gender distribution, the mean ages and BMI values were found to be similar between study and the control groups. However, due to evident growth retardation; body height, weight and BSA values of GH deficient groups were lower than those of the control subjects. GH treated groups had lower kidney length and total kidney volumes compared with their control subjects (Table 1).

Studies on rats have shown that renal growth and increased GFR can be induced in GH deficient rats by administration of GH or IGF-1.17–19 The rhGH initial ages of our patients with GH deficiency was approximately 10 years and their rhGH treatment durations were nearly 1.5 years, at first evaluation. Considering lower height and kidney size, we can say that 1.5 years duration of rhGH therapy did not sufficiently increased height and kidney dimensions. However, it has been reported that the impact of rhGH on incremental height was frequently more marked during the initial period of rhGH treatment.20

Comparing kidney volume and length of our patients using nomograms11,12 revealed that, the patients generally had low kidney volume and length by age, however kidney length by height of 89% of our patients were compatible with nomograms data. Following 3 years of rhGH replacement, all nomograms showed significantly increase in kidney sizes (Table 2). These results indicated that kidney sizes of rhGH received children were low and rhGH replacement effective on renal growth.

After 3 years of first evaluation, we re-evaluated the kidney sizes of 23 patients. Second measurements showed significantly increased body height ad mean length, depth and width of kidney and total kidney volume compared with the first measurements (Table 3). Normal and hypophysectomized rats treated with GH doses comparable with the therapeutic regimens used in children with short stature, rhGH increased renal weight indicating an isometric effect of GH on normal growth.21 Following 3 years of rhGH replacement from the first evaluation of our patients showed similar increases in percentages of height, kidney length and liver long axis (14.4%, 11.7% and 7.7%, respectively). This finding indicated that effect of rhGH treatment on kidney growth is in accordance with body height and liver. Although, the effect of rhGH in children is greatest in the first year of therapy,20 our results indicated that visceral organ growth compatible with the increase in height continue under rhGH supplementation.

Estimated GFR values of both IGHD and MPHD were found to be lower than those of their control groups. Significant increase was observed in GFR values of our rhGH received children after 3 years of rhGH replacement, compared with the first measurements of the same patients. Similarly, an increase in GFR values has been recorded in adult patients with GH deficiency following rhGH treatment.22

It has been reported that malnourished and hypothyroidic children had short stature and smaller kidneys than their healthy control subjects, and height has the strongest correlation with kidney size in malnourished children.23,24 However, we could not compare our results with the results of previous studies, since we could not see a previous study investigating effect of rhGH on visceral organ growth in children.

Although delay in GH treatment initiation and GH treatment durations were similar between patients with IGHD and MPHD, many hormonal values (IGF-1, IGFBP-3, TSH, T₃, fT₃) were found to be lower in MPHD group compared with IGHD group (data not shown). This may be due to partial GH deficiency that found in one-third of our IGHD group in contrast to more severe underlying pituitary pathologies of MPHD group.

In the present study, at first evaluation, both left and right kidney lengths and kidney volume were found as positively correlated with IGF-1 and IGFBP-3 levels. GH is the strongest secretagogue for IGF-1 and some effects of GH on peripheral organs are mediated by IGF-1 [4]. The GH/IGF/IGFBP system, including receptors of GH and IGF-1 and the IGFBPs are expressed in the kidney.14

A limitation of this study is lack of data on control subjects following 3 years, since our control group consisted of healthy children without chronic illness that necessitate long follow-up examinations, therefore we could not reach them.

In conclusion, children with IGHD and MPHD had smaller kidneys compared with their healthy controls. Growth in kidney size was parallel to increase in height and liver growth. Although all of GFR estimation results were within physiological limits, lower GFR values of patients significantly increased following 3 years of rhGH replacement. It can be concluded that rhGH had positive effects on renal growth and kidney functions as well as liver growth. The most powerful indicative of kidney size was body height in rhGH received children.

Declaration of interest

The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.