| Abstract|| |
Children with chronic kidney disease are at high risk for growth retardation and decreased adult height. Growth hormone (GH) treatment is known to stimulate growth in children with short stature suffering from chronic kidney disease. However, the extent to which this therapy affects final adult height is not known. This study was performed on 15 patients with endstage renal disease (ESRD) on regular hemodialysis to detect the effect of using recombinant human growth hormone (rhGH) on growth of patients with ESRD on regular hemodialysis and comparing this effect with the growth velocity in the same group without using rhGH in the year before therapy. There were eight females and seven males with mean age 10.6 ± 2.8 (range 5-14 years). For each patient, recombinant GH was given for one year, three-times weekly. The data of these 15 patients was compared with the year before treatment versus data of the same group of patients after six months and after one year of rhGH therapy. Our results showed that, in the year before therapy, height of these patients increased from a mean of 112.1 ± 11.6 cm to 112.7 ± 11.5 cm, which is a non-significant increase statistically (P >0.05) as well as clinically (mean growth velocity 0.6 cm/year), while height of these patients increased from a mean of 112.7 ± 11.5 cm at the start of therapy to 116.8 ± 11 cm after therapy for one year, which, although statically not significant (P >0.05), was of clinical significance as it makes rate of increase, i.e. the mean growth velocity, 4.1 cm/year close to the normal growth velocity, which is 5 cm/year, before puberty. rhGH therapy for patients with ESRD on regular hemodialysis is helpful in height gain and catch-up growth even when given three-times per week instead of five- or six-times per week. We recommend giving rhGH therapy as a routine supplementation to pediatric patients before epiphyseal closure.
|How to cite this article:|
Youssef DM. Results of recombinant growth hormone treatment in children with end-stage renal disease on regular hemodialysis. Saudi J Kidney Dis Transpl 2012;23:755-64
|How to cite this URL:|
Youssef DM. Results of recombinant growth hormone treatment in children with end-stage renal disease on regular hemodialysis. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2015 Nov 30];23:755-64. Available from: http://www.sjkdt.org/text.asp?2012/23/4/755/98157
| Introduction|| |
Growth retardation is one of the major complications of chronic kidney disease (CKD) in children. Unfortunately, treatment of end-stage renal disease (ESRD) with dialysis or with renal transplantation was also not completely successful in restoring normal growth. It is for this reason that early recognition and treatment of growth failure is so important in CKD.  In young children with CKD, the degree of protein wasting is closely correlated with serum bicarbonate levels.  Moreover, metabolic acidosis has profound suppressive effects on the somatotropic hormone axis by downregulating growth hormone (GH) secretion,  GH receptor and insulin growth factor-1 (IGF-1) gene expression  and serum IGF-1 levels. 
The multiple alterations of the endocrine systems associated with CKD have been described earlier. Of particular relevance for statural growth is the complex state of GH and IGF-1 resistance, which results in an impaired promotion of endochondral and appositional growth by IGF-1. 
In children with CKD, normal or even elevated GH is measured in serum. This is a result of a reduced metabolic clearance of GH by the kidney resulting in an increased half-life in the serum.  An increase seen during puberty is absent in patients with CKD.  The lack of response to normal or even high circulating GH indicates insensitivity to the actions of GH in peripheral tissues. In addition, a post-recaptor defect has been found in uremic animals. 
The GH resistance observed in uremia and during glucocorticoid treatment and the experimental proof that GH resistance can be overcome by supraphysiological doses of exogenous GH have provided a rationale for treating children with CKD and those undergoing renal transplantation with recombinant human growth hormone (rhGH).  Administration of rhGH raises IGF-1 production to a greater degree than it raises the insulin-like growth factorbinding protein concentrations, and there-by increases the availability of free IGF-1 at the tissue level. 
Children who received rhGH at 28 IU/m 2 /week grew (1.4 cm/year) more than those who received 14 IU/m 2 /week, but treatment with higher doses (56 IU/m 2 /week) did not result in additional growth. In addition, changes in bone age did not differ significantly between the treatment and the control groups. 
The most important side-effect of rhGH treatment is intracranial hypertension; incidence may be higher in patients with CKD.  Hyper-parathyroidism has been reported rarely,  and an extended survey of thousands of patients failed to disclose any significant relationship between GH treatment and malignancy. , Theoretically, rhGH therapy may contribute to atherosclerosis or induce diabetes mellitus by exhaustion of pancreatic beta cells, although not a single case of irreversible diabetes mellitus has been observed in CKD children treated with rhGH. ,
| Aim of the Study|| |
To detect the effect of using rhGH on growth of patients with ESRD on regular hemodialysis and comparing this with the growth velocity in the same group in the year before employing the therapy.
| Patients and Methods|| |
This is a crossover non-randomized controlled clinical trial. This was carried out in the Pediatric Department and Nephrology Unit of Zagazig University Hospital from June 2006 to June 2008.
The study was done on 15 patients with ESRD on regular hemodialysis. There were eight females and seven males aged between five years and 14 years (mean age 10.6 ± 2.8 years).
The demographic data of these patients designated as group A had been taken before initiation of rhGH therapy and at the start of treatment by rhGH designated as group B, taking patients at this period as a control group (not exposed to therapy). Data of the patients 6 months after initiation of treatment was referred to as group C, and after treatment for one year was referred to as group D. For each patient recombinant GH (somatropine) was given three times per week in a dose of 0.33 mg/kg/week (0.8 IU/kg/week) for one year after obtaining informed written consent from the parents of each patient.
Inclusion criteria were patients with ESRD below the age of epiphyseal closure. Exclusion criteria included patients with iPTH levels five-times above the upper normal level, i.e. 300 pg/dL, patients with active rickets or a slipped capital femoral epiphysis, phosphorus greater than 1.5-times the upper limit for age and those with abnormal fundus examination.
Recommendations for the use of GH for children with CKD by the National Kidney Foundation 2005 were that children should have hip X-rays and a wrist bone age performed prior to initiation of GH therapy; GH therapy should not be initiated until the PTH level is not greater than 1.5-times (450 pg/mL) the target upper limit in CKD stage 5 and until the phosphorus is not greater than 1.5-times the upper limit for age. Children receiving GH therapy in CKD stage 5 should have calcium, phosphorus, PTH and alkaline phosphatase monitored at least every month during the first six months of therapy. Children receiving GH therapy should have a wrist bone age performed yearly.
Hip X-rays should be performed when clinically indicated. 
All patients were subjected to thorough history taking, anthropometric measurement [height, weight, mid arm circumference (MAC)], routine clinical examination and routine laboratory examination (serum creatinine, blood urea nitrogen, serum albumin, hemoglobin, serum calcium and serum phosphorus).
Fundus examinations were done at the start of therapy and regularly every three months after that. Fasting blood sugar was done for every patient once per month during the period of therapy. X-ray was done at the start of therapy of hip joint, and we did not need to repeat it as there was no clinical indication for the same.
| Statistical Analysis|| |
Statistical analysis was performed using a computer-based program (SPSS version 11). The quantitave data are presented as mean ± standard deviation. Unpaired independent t test was used as the statistical test of significance for two groups, Paired t test for paired quantitave data for more than two groups ANOVA test was used as the test of statistical significance. A P-value less than 0.05 was considered as statistically significant.
| Results|| |
The study was done on 15 patients with ESRD. There were eight females and seven males with a mean age of 10.6 ± 2.8 years, with mean duration of dialysis 3.03 ± 1.7 years [Table 1]. [Table 2] shows the etiology of CKD among the study group. [Table 3] shows those patients on regular dialysis and taking usual routine care of ESRD during the one year period before starting rhGH therapy till the day of start of rhGH therapy. There was no increase in the anthropometric measurements as their mean height just raised from 112.1 ± 11.6 cm to 112.7 ± 11.5 cm (0.6 cm/year), their weight from 19.2 ± 6.2 kg to 21.2 ± 4 kg (2 kg/year) and MAC from 14.9 ± 1.6 cm to 15.2 ± 1.8 cm (0.3 cm/year). This increase was neither statistically nor clinically significant.
|Table 3: Comparison between data of the studied group before therapy by one year (A) and on starting treatment (B).|
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[Table 4] shows increase in height from 112.7 ± 11.5 cm at start of therapy to 114.1 ± 11 cm after six months of therapy, i.e. (1.4 cm in six months and growth velocity of 2.8 cm/year), and increased to 116.8 ± 11 cm after one year of therapy, i.e. 2.7 cm in six months or growth velocity in the second six months of therapy of 5.4 cm/year, also indicate increase by 4.1 cm during one year on therapy.
|Table 4: Comparison of anthropometric measurement through the progression of rhGH therapy in the study group at start of treatment (B) and after 6 months of therapy (C) and after 1 year of treatment (D).|
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Also, this table shows an increase in weight in the first six months of therapy from 21.2 ± 4 kg to 21.7 ± 4.1 kg (weight velocity 1 kg/year) and to 22.5 ± 4.1 kg after another six months (0.8 kg in the second six months, weight velocity 1.6 kg/year) and growth velocity (1.3 kg/ year in one year on therapy), which indicates decreasing effect on weight with time. The MAC increased from 15.2 ± 1.8 cm at the start of therapy to 16.2 ± 1.7 cm after six months of therapy, i.e. 1 cm in six months (MAC velocity 2 cm/year) in the first six months of therapy and further increased to 16.8 ± 2.1 cm after one year of therapy, i.e. 0.6 cm gain in the second six months (MAC velocity 1.2 cm/ year in the second six months), amounting to a MAC velocity of 1.6 cm/year after one year of therapy, which indicates decreasing effect of rhGH with time. However, none of these increases in height, weight and MAC were statistically significant (P >0.05).
[Figure 1] shows that the height increased from a mean of 112.1 ± 11.6 cm one year before therapy to 112.7 ± 11.5 cm (0.6 cm/year), which is a non-significant increase statistically or clinically, while height of the studied group increased from a mean of 112.7 ± 11.5 cm at the start of therapy to 116.8 ± 11 cm one year after starting therapy, which, although is not statistically significant, was of clinical significance, and denotes that this rate of increase (4.1 cm/year) is not the usual gain in height in such patients as this rate was only 0.6 cm/year in the year before therapy.
|Figure 1: Comparison of the difference in height gain from period one year before treatment (A) and at start of treatment (B) and gain in height from the start of treatment (B) and one year after therapy (D).|
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[Figure 2] shows that weight increased from a mean of 19.2 ± 6.5 kg one year before therapy to 21.2 ± 4 kg at the start of therapy (2 kg/ year), while it increased from a mean of 21.2 ± 4 kg at start of therapy to 22.5 ± 4.1 kg after therapy by rhGH (1.3 kg/year), which indicates the main effect of growth hormone in linear growth and height rather than in weight gain.
|Figure 2: Comparison of difference in weight gain from period one year before treatment (A) and at start of treatment (B) and gain in height from the start of treatment (B) and one year after therapy (D).|
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[Figure 3] shows gain in MAC from a mean of 14.9 ± 1.6 cm one year before therapy to a mean of 15.2 m at the start of therapy (0.7 cm/ year), while the gain was from a mean of 15.2 ± 1.8 cm at start of therapy to a mean of 16.8 ± 2.1 cm after therapy by one year (1.6 cm/year), indicating the good effect of growth hormone therapy on MAC, which is a good marker of nutrition state as well as growth.
|Figure 3: Comparison of difference in MAC gain from period before treatment by one year (A) and at start of treatment (B) and gain in height from the start of treatment (B) and one year after therapy (D).|
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[Table 5] shows no significant difference in the laboratory results of serum albumin, blood urea nitrogen, serum creatinine, serum calcium, phosphorus and hemoglobin of our patients throughout the period of therapy (P >0.05), while there is a significant increase in iPTH level as it was raised from a median of 90.4 pg/mL to 455.1 pg/mL after six months of therapy and 730.7 pg/mL after one year of therapy, denoting the major effect of growth hormone in increasing iPTH level.
Our patients were subjected to fundus examination before treatment and regularly every three months, but none showed any sign of increased intracranial tension. Similarly, regular testing for fasting blood sugar was done every month and there was no case of hyperglycemia. Also, X-rays of the hip joint were taken at the start to exclude any abnormality, and we did not have to repeat them as there were no clinical signs of femoral head necrosis or slipped femoral head in our cases.
| Discussion|| |
The pathogenesis of impaired growth in CKD is complex and only partially understood. Although a particular cause can occasionally be found, a combination of several factors is generally responsible for growth impairment. Furthermore, the patient's age; the type, duration and severity of renal disease; the treatment modality; and the patient's social environment play important roles.  Before the introduction of therapy with rhGH, stunting was frequently seen in children with CKD. The EDTA registry has documented a diminished final height in 50% of the patients. And, the mean final height was lower in patients with congenital renal disorders. 
In our study, we found that in the period from July 2006 to July 2007, without use of rhGH, our patients gained only a mean of 0.6 cm/year in height and mean of 0.3 cm/year in MAC, which expresses marked growth failure in those patients, although they were taking usual and routine care of ESRD and were on regular hemodialysis. A mean weight gain of 2 kg/ year indicates that those patients were taking near-normal appropriate nutrition, but, in uremic children, the initiation of dialysis usually does not improve growth. 
In pre-pubertal children with predialytic CKD, numerous studies, including two double-blind placebo-controlled trials, demonstrated that rhGH induces a nearly two-fold increase in height velocity during the first treatment year, with a diminishing but still significant effect on growth rate during the second year. ,, The average benefit in final height seems to be 1- 1.5 SDs, although the range of height gained in these studies was only 2 and 10 cm. Untreated children with CKD experience a loss in relative height, which should be added to absolute height gain to fully appreciate the efficacy of rhGH treatment. In a prospective multicenter trial in Germany, the mean adult height was 165.2 cm in boys and 156.2 cm in girls in rhGH-treated patients and significantly greater than in untreated controls; two-thirds of the treated children reached an adult height above the 3 rd percentile, but the mean adult height was still more than 10 cm below the genetic target height. 
In the current study also, the 15 patients with ESRD after receiving rhGH started gaining height in a mean velocity of 4.1 cm/year, i.e. their mean height increased from a mean of ± 11.5 cm at the start of treatment to 116.7 ± 11.1 cm after one year of therapy, and this is close to the normal velocity, which is 5 cm/year.  In pre-pubertal children also, growth outcomes across trials were similar to a study that was conducted in the year 2001. Comparing those under rhGH therapy with patients who received placebo or no treatment, those who received rhGH had mean adjusted height increases of 5.7 cm/year at six months, 4.1 cm/year at one year and 10.9 cm/year at two years.  This is also into keeping with Heffner and Schaefer, who described controlled and uncontrolled studies in children with CKD and uniformly demonstrated the efficacy of GH therapy, resulting in catch-up growth and an average height improvement of +2 SDs. During the first year of treatment, growth is often dramatic. 
Although our study showed increasing growth velocity over time, after six months, the mean increase was only 2.8 cm/year from 112.7 ± 11.5 to 114.1 ± 11 and after one year of therapy the mean increase was 4.1 cm/year from 112.7 ± 11.5 to 116.8 ± 11.1. This is contrary to other studies, and shows that the rate of increase in growth velocity decreases with time of therapy, similar to the findings of Mehls and Ritz.  A symposium by the Food and Drug administration in 1987 for the use of supraphysiological doses of rhGH in growth retarded children with CKD published the initial six month data of five children with CKD treated with rhGH.  The annual growth velocity increased from 4.94 ± 1.4 cm/year for the year before treatment to 10.08 ± 1.97 cm/ year after treatment (P <0.01). A subsequent report published in 1989  noted that the actual velocity after one year of treatment in these five children was 9.8 ± 1.2 cm/year (P = 0.006). The long-term (3 years) outcome of nine patients with CKD treated with rhGH, which included the five children from the previous reports,  indicated that the acceleration in growth velocity continues during the second and third year of therapy. The mean velocity of these nine children increased from 5 ± 1.4 cm/year to 8.5 ± 1.3 (P = 0.0001), 8.2 ± 1.8 (P <0.004) and 8.1 ± 1.3 (P <0.05) cm/year after 12, 24 and 36 months of rhGH treatment, respectively, as height velocity with rhGH treatment decrease over time underscores the importance of long-term observations and raises the question about an improvement in the final adult height compared with untreated controls.  This discrepancy between our results and published data may become clearer with longer period of therapy.
In the current study, the MAC increased from 15.2 ± 1.8 cm at start of therapy to 16.2 ± 1.7 cm after six months of therapy (2 cm/year) and to 16.8 ± 2.1 cm after one year of therapy (1.3 cm/year). Because MAC is a good marker of growth, this shows the beneficial effect of rhGH on growth. This effect decreases with time from 2 cm/year to 1.3 cm/year. Longterm studies that followed-up patients with CKD till adulthood also showed that the effect seems to be significantly diminished in the following years. 
As rhGH hormone enhances short-term growth in children with CKD, but the effect on adult height is unknown, and optimal doses and the time to start rhGH treatment remain uncertain,  we used rhGH in a dose of 0.33 mg/kg/ week (0.8 IU/kg/week), which is the suggested dose by most of the literature.  A daily subcutaneous dose of 4 IU/m 2 had been recommended, and was found to be more efficient than 2 IU/m 2 and equally effective as 8 IU/m.  Similar results were published by others, which showed that a curvilinear dose-response relationship appears to exist. However, a dose of 4 IU/m 2 /day was more efficient than 2 IU/m 2 / day in a double-blind trial,  and no further improvement of the growth response was observed with 8 IU/m 2 /day, at least in a pubertal cohort.  We gave the total weekly dose in three divided doses instead of five days per week for the following reasons: (a) as there is no evidence-based protocol of rhGH administration till now, we tried to use the most appropriate method that will keep patient compliance, (b) it was more convenient to our patients as it will be on days of dialysis sessions, (c) these children are on many other medications and rhGH is a subcutaneous injection many can take only from the hospital and (d) its effect is not seen instantly and patients have to wait at least six months to feel the effect of therapy.
Our study shows no significant increase in weight after rhGH therapy, as weight increased from 21.2 ± 4 kg to 21.7 ± 4.1 kg after six months and to 22.5 ± 4.1 kg after one year, which means a mean of 2.3 kg/year, indicating that GH might help in weight increase but nutritional care will remain the main controller of weight. The first principle of treatment of growth failure in CKD is to assure adequate caloric intake as this is most crucial in the first two years of life, and catch-up growth can often be observed if there was preexistent malnutrition.  By comparing the rate of increase in weight in the year without therapy in which our patient's weight increased from 19.2 ± 6.5 kg to 21.2 ± 4 kg at the start of therapy (2 kg/year) means that the nutritional care given to those patients and adequate routine therapy of CKD are the main determinants of the weight gain and growth hormone therapy affect it only to a minor degree in comparison with height velocity effect.
In our study, using rhGH laboratory results of albumin, blood urea nitrogen, serum creatinine, calcium and phosphorous in the fifteen patients through the year of therapy were not affected significantly, and this shows that side-effects of rhGH therapy did not include alteration of these laboratory values.  Concern has been raised that GH may cause glomerular hyperfiltration and accelerated deterioration of renal function. However, the physiologic acute increase in GFR induced by GH in healthy subjects is obliterated in patients with CKD,  and as we started using therapy in patients with ESRD, i.e. GFR <10 mL/1.73 m 2 /min; therefore, we did not see any statistically significant effect on serum creatinine.
Although we were following the National Kidney Foundation recommendation with regard to iPTH levels during therapy (to be below 900 pg/mL),  as our patients came in stage 5 CKD, there was a significant rise in iPTH level as it was elevated from a median of 90.4 (5.04-914) pg/mL at the start of therapy to 455.1 (9-1068) pg/mL after six months and to 730.7 (10-2850) pg/mL after one year of therapy, which is statistically significant (P <0.05). This confirms that rhGH raises level of iPTH. , Therefore, we recommend close follow-up of iPTH levels and readjustment according to the National Kidney Foundation recommendation published in 2005, in stopping and restarting the treatment according to iPTH level to avoid aggravation of renal ostedysterophy. 
As regards the other side-effects of rhGH therapy, viz. the increased intracranial tension as GH induces an IGF-1-mediated increase in distal tubular sodium reabsorption and upregulates the renin-angiotensin system, , and, as a consequence, a transient, usually mild retention of sodium and water occurs during the first few days of treatment. In this context, benign intracranial hypertension has been reported as a rare adverse effect of GH treatment in patients with various underlying diseases. In CKD, the risk for this complication is increased ten-fold. , In one survey, signs or symptoms of intracranial hypertension were noted in 15 out of 1670 patients with renal disease receiving rhGH (0.9%).  All but two patients were symptomatic; the symptoms generally abated when GH therapy was discontinued, but two patients had persistent blindness. Four of these patients experienced recurrence of intracranial hypertension after re-initiation of GH therapy. Intracranial hypertension manifested within a median of 13 weeks of treatment and therefore it is recommend to perform a baseline funduscopy and gradually increase the dose from 50% to 100% of the maintenance dose in about four weeks.  The risk-benefit ratio should be evaluated carefully when considering re-initiation of rhGH treatment after reversal of symptoms. ,,, But, in our study, none of the 15 patients showed any signs of increased intra-cranial tension in fundoscopic examination, which was performed every three months or at the time of having any clinical symptoms. This can be explained by the fact that we controlled the hypertension and hydration state of those patients in our study as hypertension and fluid overload may be predisposing factors. The state of hydration should be well controlled at the start of treatment  as it is the most common side-effect of rhGH .  We did not face it in our patients, and we recommend very close monitoring of hypertension and for signs such as headache, vomiting and other clinical signs of increased intracranial hypertension mandating careful clinical investigations, including fundoscopic examination. Also, with regard to other complications such as slipped femoral head and epiphyseal slipping,  and femoral head necrosis  during the follow-up of our cases through one year of therapy, we performed X-ray hip at the start and at each 6 months, and there were no cases detected, and this comes in agreement with what has been reported that it is rather a rare complication. 
In this study, follow-up of blood sugar levels were done by doing fasting blood sugar every month. Normal blood sugar values were found in all cases similar to other studies, which also failed to prove this side-effect in patients with CKD under treatment by rhGH. ,,
No cases of malignancy were detected in our study, and this is also in agreement with other studies that also did not find this complication. 
In our study, we found that giving rhGH to children with ESRD under regular hemodialysis helps them to catch up their growth as their height increased about 4.1 cm/year and that even when we gave it three-times per week instead of five or six days as done in other studies, the effect on height was almost the same. Therefore, we feel that this can be recommended as a routine support to those patients.
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Doaa Mohammed Youssef
Department of Pediatrics, Zagazig University, Zagazig
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]