Biomedical Journal of Indonesia Vol 7 Issue 3 2021
The Effectiveness of Giving Growth Hormone to Children with Chronic Kidney Disease: Systematic Literature Review
Irhamni Nur Afdhila1, Fitrisia Amelin2*, Gardenia Akhyar3
1Medical Education Program, Faculty of Medicine, Universitas Andalas, Padang
2Department of Pediatricts, Faculty of Medicine, Universitas Andalas, Padang/RSUP Dr M Djamil
3Department of Dermatovenerology, Faculty of Medicine, Universitas Andalas, Padang/RSUP Dr M Djamil
A R T I C L E I N F O Keywords:
Growth Hormone Children
Chronic Kidney Disease Effectiveness
Corresponding author:
Fitrisia Amelin E-mail address:
All authors have reviewed and approved the final version of the manuscript.
https://doi.org/10.32539/BJI.v7i3.537
A B S T R A C T
Chronic Kidney Disease (CKD) can cause growth problems in children. This condition will affect children’s social life and increase morbidity and mortality. Growth hormone (GH) is one of medication that has been used for treatment of impaired growth in children with chronic kidney disease. In Indonesia, this management has not been provided, because it is expensive and its effectiveness is uncertain. Thi s research was conducted to determine the effectiveness of growth hormone in increasing linear growth in children with CKD. This study is a systematic review of the Randomized Controlled Trial (RCT) study to determine the effectiveness of growth hormone as a treatment for children with CKD. Literature search was conducted using five databases, namely Pubmed, Google Scholar, DOAJ, BMC and CENTRAL that matched the inclusion and exclusion criteria. The guide used in the literature selection was the PRISMA flow chart. A Total of 10 studies were included in the systematic review. Growth hormone is effective in increasing linear growth in children with CKD. Generally there was a significant increase in height (standard deviation (SD)), high velocity (SD or cm) in the therapy group compared to the control group. The dose of growth hormone that is given varies, but the most is 4 IU / m2 / day, once a day, by subcutaneous injection. The duration of growth hormone administration varied from 6 months to 5 years with an average of 1.7 years. Growth hormone did not aggravate kidney problems in children with CKD and can increase important factors in bone formation, namely alkaline phosphatase and osteocalcin.
1. Introduction
According to Kidney Disease Improving Global Outcome (KDIGO), chronic kidney disease (CKD) is a kidney disorder in the form of structural and kidney function abnormalities that occur for more than 3 months and affect health, with or without a decrease in the glomerular filtration rate (GFR). 1
CKD is a serious health problem in children, with increasing morbidity and mortality, as well as causing significant economic and social problems.2 The results of the Global Burden of Disease (GBD) study , in general, the incidence of CKD has increased significantly in the last 27 years. CKD became the 18th leading cause of death in the world in 2016, where previously it was ranked 27th in 1990.3 The
exact incidence rate in children is very limited, it is estimated that the incidence of CKD in children is higher than the existing data, because there are many cases that do not occur. not detected.2
In Europe, the incidence of CKD in children was about 12 out of a million population in 2008. This number is comparable to the population in other western countries.5 Research in Iran in 2011, there were 16.8 out of one million children with chronic kidney disease with a mortality rate of 18.4%.
Younger age is a predictor of death.6 In 2008, approximately 9 out of a million children underwent renal replacement therapy worldwide.4 In Indonesia, there is no national data on the incidence of CKD in children. According to data from RSCM Jakarta,
Biomedical Journal of Indonesia
Journal Homepage: https://www.jurnalkedokteranunsri.id/index.php/BJI/index
found 382 CKD patients who seek treatment at the Department of Pediatrics in 2006 and 2007. At RSUP dr. Kariadi during the 2015-2017 period, there were 566 pediatric patients with kidney disorders who came for treatment, 37.6% of them were children aged 5-12 years, 29.4% were children under five, and 29% were teenagers. 7
CKD in children is one of the diseases associated with growth disorders in children.8 The cause of this growth multifactorial disorder, ga ngguan nutritional intake, metabolic acidosis which would induce the degradation of proteins, causing muscle wasting, production of endogenous corticosteroids and organ resistance to growth hormone. In addition, decreased kidney function in CKD children results in decreased renal phosphate excretion and impaired gastrointestinal calcium reabsorption , resulting in hyperphosphatemia and hypocalcemia. Low calcium in the blood stimulates parathyroid hormone to take calcium from the bones into the blood. This is very dangerous for the integrity and growth of the child's bones.9 Growth problems in CKD children last for a long time, so it can affect linear growth which is a manifestation of long-term growth disorders. 10
Linear growth disorders in CKD children must be intervened immediately so that there is no severe loss of height in adulthood.9 Various approaches are needed in the management of linear growth disorders in children with CKD.11 Supplementation of protein and calories alone is not enough to control malnutrition and growth disorders in CKD children, special therapeutic interventions also need to be given.12 One of the special interventions that has been studied is the administration of growth hormone in CKD children. 8 The administration of growth hormone in CKD children has been recommended in several countries, and has been approved for use by the Food and Drug Administration (FDA).8.13 However, in Indonesia, the administration of growth hormone has not been used as the main therapy to improve height and weight in children with CKD, because the price of growth hormone is expensive and its effectiveness in treating linear growth disorders in children with CKD is still
uncertain. Growth disorders in CKD children in Indonesia are only given general management, such as improving nutrition, giving vitamin D, low- phosphate nutrition and phosp
hate binders, and preventing anemia progression.13Assessment of the effectiveness of growth hormone as therapy in children with CKD needs to be done, through direct research by giving growth hormone to children with CKD. This research has been carried out and is still being carried out today. However, each study was conducted with different methods and obtained different research results, which raises doubts.
A further literature concerning the role of growth hormone in children with CKD are needed to compare the differences in each study. Primary literature with RCT studies is one of the best sources for conducting such literature reviews. O leh therefore, researchers are interested in creating a literature review entitled
" Effective Provision of Growth Hormone in Children with Chronic Kidney Disease Study Randomized Controlled Trial (RCT): a Systematic Literature Review.
2. Research Methods
This research is a literature review with a systematic literature review on the effectiveness of growth hormone in children with chronic kidney disease (CKD). The sources taken are primary literature found in pubmed, google scholar, DOAJ, BMC, CENTRAL, with the keywords "chronic kidney disease or renal insufficiency chronic and child or child health and growth hormone or human growth hormone and stunting or growth disorder".
The research taken is research that meets the inclusion and exclusion criteria based on the PICOS framework. Inclusion criteria: RCT study in English, focusing on CKD children receiving growth hormone, there is a comparison/control group and the results are the effect of hormone administration on CKD children's height and the full text can be downloaded.
Exclusion criteria: studies that focus on other diseases and studies where other interventions are
more dominant.
The literature selection process uses a flow chart of preferred reporting items for systematic reviews and meta-analyses (P RISMA), and the quality of the selected studies is assessed using The Joanna Briggs Institute (JBI) critical appraisal for randomized
controlled trial, which consists of 13 questions. Each question is given a score of “1” for a yes answer, and a score of “0” for a no or unknown answer. The literature to be extracted and analyzed is literature with a total score of 7 (percentage >50%).
3. Results
Literature Selection Results
Figure 1. Literature Selection Results
A total of 11 primary articles were obtained after selecting the PRISMA flow chart. The article is first assessed for quality using JBI critical appraisal. The results of the study quality assessment are two studies with a score of 11, one study with a score of 10, one study with a score of 9, two studies with a
score of 8, four studies with a score of 7, and one study with a score of 4. were included because the percentage did not exceed 50%, so the total studies to be extracted and analyzed were 10 studies.
14,15,16,17,18,18,20,21,22,23,24
Id en ti fic ati on Sc ree n in g Fea si b ili ty In cl usi on
Study results identified through database
search (total=39) DOAJ (n=6), BMC (n=4)
Pubmed (n-16) Google Schoolar (n=11)
CENTRAL, (n=2)
DATABASE SEARCH (Total=39)
Identified from
preliminary studies (n=2)
selection result after duplicate article is deleted (n=36)
Study (full text) assessed feasibility (n=21)
Study executed because:
title and abstract do not match (n=9)
no full text (n=5) not in English (n=1)
DATABASE SEARCH (Total=39)C
Studies included in systematic review
(n=11)
Study executed because:
Thesis (n=1) Case report (n=3) irrelevant study (n=6)
DATABASE SEARCH
(Total=39)C
475
Data Extraction Results
Table 1. The Effect of Growth Hormone on Height in CKD Children
No. Researcher Name Year Result
(Height)
1. Guest G. et al; Prancis30 1998 Height (SD) increased statistically significantly in the therapy group compared to the control group
High speed (cm/year) increased statistically significantly in the therapy group compared to the control group
2. Fine RN, et al; Amerika34 2002 Height (SD) increased statistically significantly in the therapy group compared to the control group
3. Koelega ACS, et al; Belanda35 1991 High speed (cm/6 months) increased
statistically significantly in the therapy group compared to the control group
4. Darabi A, et al; Iran27 2019 Height (SD) increased statistically significantly in the therapy group compared to the control group.
5. Dyck MV, et al; Belgia29 2001 Height (SD) increased significantly in the therapy group compared to the control group.
6. Koelega ACS, et al; Belanda37 1994 High speed (SD) increased clinically
significantly in the therapy group compared to the therapy and control group
7. Sluis IM, et al; Belanda32 2000 Height (SD) increased statistically significantly in the therapy group compared to the control group
8. Hertel NT, et al; Denmark36 2002 Height (sd) increased in both groups, there was no clinically significant difference between both of them.
High speed (sd) increased in both groups, there was no clinically significant difference between boh of them
9. Mencarrelli F, et al Italia28 2009 Height (sd) increased statistically significantly in the therapy group, there was no difference between the therapy and control groups 10. Haffiner D, et al; Jerman 31 2000 Height (SD) increased statistically significantly
in the therapy group compared to the control group
Table 2. Dosage, frequency, method of administration, and duration of administration of growth hormone in children with CKD
No. Researcher
Name Year Dosage Frequency Method of
Administration Duration 1. Guest G. et al;
Prancis30 1998 30 IU/m2/week equal to
4.2 IU/m2/day Once a day Subcutaneous
injection 1 years 2. Fine RN, et al;
Amerika34 2002 0.05 mg/kg/day equal
to 4 IU/m2/day Once a day Subcutaneous
injection 1 years 3. Koelega ACS, et
al; Belanda35 1991 4 IU/m2/day Once a day Subcutaneous
injection 6 months 4. Darabi A, et al;
Iran27 2019 4 IU/m2/day Once a day Subcutaneous
injection 2 years 5. Dyck MV, et al;
Belgia29 2001 1 IU/kg/week equal to
0.14 IU/kg/week Once a day Subcutaneous
injection 1 years 6. Koelega ACS, et
al; Belanda37 1994 4 IU/m2/day and 2
IU/m2/day Once a day Subcutaneous
injection 2 years 7. Sluis IM, et al;
Belanda32 2000 4 IU/m2/day Once a day Subcutaneous
injection 2 years
No. Researcher Name
Year Dosage Frequency Method of
Administration
Duration
8. Hertel NT, et al;
Denmark36 2002 4 IU/m2/day and 2
IU/m2/day Once a day Subcutaneous
injection 1 years 9. Mencarrelli F,
et al Italia28 2009 0.05 mg/kg/day equal
to 4 IU/m2/day Once a day Subcutaneous
injection 2 years 10. Haffiner D, et
al; Jerman 31 2000 1 IU/kg/week equal to
0.14 IU/kg/week Once a day Subcutaneous
injection 5 years
Table 3. Safety of Giving Growth Hormone to CKD Children
No. Researcher Name Year Result
(Height)
1. Guest G. et al; Prancis30 1998 Serum creatin increased slightly, but there were no significant differences between the therapy and control groups
Inulin clearance decreased slightly, but there was no significant difference between the therapy and control groups
1 patient in the therapy group with side effects of papilledema
2. Fine RN, et al; Amerika34 2002 There was no significant difference in serum creatinine between the two groups
3. Koelega ACS, et al; Belanda35 1991 No explanation
4. Darabi A, et al; Iran27 2019 GFR was slightly improved in the therapy group but was not significant
5. Dyck MV, et al; Belgia29 2001 Creatinum clearance was no significant difference between the two groups 6. Koelega ACS, et al; Belanda37 1994 No explanation
7. Sluis IM, et al; Belanda32 2000 GFR there was no significant difference between the two groups
8. Hertel NT, et al; Denmark36 2002 GFR there was no significant difference between the two groups
9. Mencarrelli F, et al Italia28 2009 No explanation 10. Haffiner D, et al; Jerman 31 2000 No explanation
4. Discussion
Growth Hormone Disorders in Children with CKD
Growth hormone is secreted by the anterior pituitary gland under stimulation by growth hormone releasing hormone (GHRH) from the hypothalamus.
This growth hormone will bind to its receptors and activate insulin growth factor-1 (IGF-1) in tissues, which is a precursor for cartilage growth, cell replication, protein synthesis, and carbohydrate balance. IGF-1 produced in some tissues will be released in the blood. Generally, this IGF-1 binds to insulin growth factor binding protein (IGFBP).25
However, IGF-1 which is not bound to IGFBP (free IGF-1), is more effective than bound IGF-1. In children with chronic kidney disease (CKD), IGF-1 does not work optimally, because the kidney's ability to excrete IGFBP is reduced, so circulating IGFBP increases which causes bound IGF-1 to increase and free IGF-1 to decrease. 25,26 In addition, another cause of IGF-1 function is not optimal in CKD children due to impaired signal transduction through janus kinase 2/signal transducer and activator transcription5 (JAK2/STAT5), which is a growth hormone intermediary to activate IGF-1. which can be seen in Figure 2 27
477
Figure 2 . 27 . Transduction Disturbance Mechanism
The Effect of Growth Hormone on Children with CKD . Height
Giving growth hormone is part of the management of growth disorders in CKD children. Growth hormone affects the balance between IGF-1 which stimulates growth and inhibits IGFBP, so that the ratio of IGF-1/IGFBP increases. 28 In a review that has been conducted, several studies have shown a significant increase in IGF-1 in the treatment group compared to the control group. 16,17,18,19,22,23
Growth hormone is effective in correcting linear growth disorders in CKD children. This can be seen from the increase in height from eight studies as well as significant differences between the therapy group and the control group. 14,15,17,18,19,20,21,22,23,24 In children who were intervened with growth hormone for 1 year, the results were found to be effective in increasing height in all studies. 14,15,18,23 A study conducted on thirty prepubertal CKD children, it was found that the height of the intervention children increased by 0.98 standard deviations (SD), inversely proportional to the unintervened group, the height decreased by 1.02 SD . This study is the best result of all studies conducted for 1 year.18
In addition to height in SD units, linear growth can also be assessed from high speed. An ak PGK who intervened, high-speed increase of 3.6 cm / year, with an increase of 3.2 cm greater than the control group.
14 Response to growth hormone administration was also effective in increasing height during 2 years of treatment in all studies. 17,19,20,22 The best study results showed an increase in the height of CKD children in the therapy group reaching 1.39 SD, while in the control group it decreased by 0.07 SD.22
There are two studies where there is a significant increase in height in the treatment group, but there is no significant difference when compared to the control group. These results were obtained in the research of Hertel et al. and Mencarrelli et al. 20,23 In Hertel et al's study, there may be no significant difference, because the control group taken was the group that was still given a lower dose of growth hormone, namely 2 IU/m²/day , while the therapy group was 4 IU/m²/day, so that the hormone This low dose growth rate still has an effect on the height of CKD children.23 The Mencarelli et al study, which was conducted on infants with CKD or with end-stage renal disease (ESRD) who had received growth hormone before 1 year of age, probably did not show a significant difference in infant height between the treatment and control groups. , because in addition
to giving growth hormone, nutritional intake of infants was also considered in both groups. 20 Adequate nutritional intake is the most important factor for achieving normal growth and body composition in infants with CKD. Growth hormone can be used as a secondary treatment in CKD infants.
If the baby receives growth hormone therapy, it is recommended that it be followed by adequate nutrition, so that the effect of growth hormone therapy is more optimal. 29
During puberty, the height increase of CKD children is not as good as that of normal children, due to the fact that in CKD children the growth acceleration process is delayed and shortened, so that the use of puberty is not optimal.30 In the literature review that has been carried out, there are no studies that specialize in research on pubertal children. However, there is one study that compared the increase in height of CKD children with growth hormone intervention during prepubertal and pubertal periods. This study was a cohort study (5 years), which showed that the increase in height in CKD children who were intervened with growth hormone in the prepubertal period was better than during puberty. 21
CKD children receiving dialysis therapy had worse growth retardation than CKD children without dialysis, although growth rates increased after transplantation.31 Research in children who received kidney transplants, found a good response to the administration of growth hormone. The ratio of children's height given the intervention also increased significantly from the children without intervention, and the administration of growth hormone did not affect the condition of the transplanted kidney.14,15 However, when this study is compared with other studies, it appears that studies devoted to children who received transplants showed that the increase in average height was not as good as the others.
The most important height result is final height or adult height. Data on CKD children who were given growth hormone for 5 years and followed until they reached their final adult height showed that CKD children who were intervened had maintained the process of pursuing growth, while CKD children who did not receive therapy experienced progressive growth failure. Final adult height in intervention children was -1.6 1.2 SD and -2.1 1.2 SD in children without intervention. 21
Dosage, Frequency, Method of Administration, and Duration of Administration of Growth Hormone in CKD Children The results of the RCT reviews that have been carried out give the impression that CKD children should be given growth hormone at a dose of 4 IU/m²/day, because many studies have conducted experiments with this dose. 14,15,16,17,19,20,22,23 Doses of 4 IU/m²/day are considered more effective in increasing height than doses of 2 IU/m²/day. In children who were intervened with growth hormone 2 IU/m²/day for 2 years, the increase in height that balanced the dose of 4 IU /m²/day was only in the first 6 months, then 1.5 years after that the process of pursuing growth stopped. Height velocity increased from -3.6 SD to 2.3 SD at intervention 4 IU/m²/day and at intervention 2 IU/m²/day increased from -2.7 SD to 0.4 SD. There was a 2.8 SD greater difference in the high-speed increase at a dose of 4 IU/m²/day.
19 This conclusion was drawn based on seven studies. This is because the study did not show significant differences in larger doses, da n two other studies to show that the dose with a different unit IU / kg / week and IU / m 2 / week. 18,21,23
The frequency and method of administration of growth hormone in all studies were the same, namely once a day and given by subcutaneous injection. The duration of administration of growth hormone varies, some are researched for 6 months, some are 5 years, and the most are 1 year and 2 years. There was no effect of duration of administration on the magnitude of the difference in height between the therapy and control groups. 14,15,16,17,1 8,19,20,21,22,23
In several reviews, there is a pattern that shows the effect of growth hormone begins to fade with a longer duration of treatment. 18,19,20,22 For example, the increase in height of CKD children who received growth hormone for the first six months was 0.57 SD, 0.41 SD for the second six months, and 0.15 SD for the third six months, and 0, 08 SD for the last six months. 18 The time dependence of the effectiveness of this growth hormone cannot be concluded with certainty, because not all data are supportive and sufficient to draw conclusions. So, determining how long to give growth hormone is recommended by evaluating the patient's height every 6 months.
Safety of Giving Growth Hormone to CKD
Children
1. Kidney
The metabolic products of growth hormone, namely growth hormone, growth hormone receptors, IGF-1 and IGF-1 receptors are expressed in kidney tissue. 32 Under normal circumstances, most of the metabolic by-products of this growth hormone are cleared in the kidney, taking advantage of efficient glomerular filtration and extensive degradation by the kidney. 33 In children with CKD there is a decrease in glomerular filtration rate (GFR), which led to the disruption of the metabolic excretion of growth hormone. This disorder may affect or aggravate the condition of the kidneys. 32
The safety of growth hormone on the kidneys can be seen by assessing kidney function, namely from serum creatinine, inulin clearance , creatinine clearance and GFR. Inulin and creatinine can be used as a basis for assessing GFR because almost all of them are excreted in the kidneys. 33 In the review that has been carried out, there are five studies that show no significant change in the value of the kidney function. 15,17,18,22,23 Emp at the study did not address the results of the kidney function.
16,19,20,21 One study showed an increase in serum creatinine followed by a decrease in inulin clearance
, but the difference was not significant between the treatment and control groups.14 However, the results of this study cannot be concluded, because the increase in serum creatinine is not only caused by impaired excretion of creatinine through urine, but can also be caused by an increase in creatinine production. In CKD children who receive growth hormone, there can be an increase in muscle mass so that muscle metabolism that produces creatinine
also increases.34
2. Other Organs
Side effects of giving growth hormone in other organs in the study of Guest et al for 1 year, one patient had papilledema, without symptoms of benign intracranial hypertension (BIH).21 Papilloedema is swelling of the optic nerve due to increased intracranial pressure.35 The diagnosis in this study was made on the basis of routine ophthalmologic examinations, where papilledema resolved after discontinuation of growth hormone therapy. Even so, it cannot be concluded that growth hormone causes abnormalities in the eye. 21 Another non-RCT study, which followed 30 patients who received growth hormone and underwent routine eye examinations, found no eye abnormalities in the children studied.36
3. Parathyroid Hormone
The effect of growth hormone on parathyroid hormone is still uncertain. The indirect effect of growth hormone is on the excretion of phosphate.
Growth hormone has antiphosphaturic properties, so it can increase phosphate levels in the body.
Increased phosphate in the body, stimulates parathyroid hormone to work to inhibit reabsorption of phosphate in the kidneys.37 Studies Guest et al and Mencarrelli et al, showed that parathyroid hormone increased in the treatment group, but the increase was not significant.14.20
Parathyroid hormone acts on the kidneys by inhibiting the reabsorption of phosphate and stimulating calcium reabsorption in the kidneys. In addition, parathyroid hormone also works indirectly by stimulating the 1 hydroxylase enzyme in the kidneys which is responsible for the formation of active vitamin D3. Vitamin D3 can increase calcium absorption in the small intestine. With this way of working, a slight increase in parathyroid hormone cannot be said to be a problem in a person's body. 38 However, an excessive increase in parathyroid hormone is also a sign of kidney disorders.39
Effect of Growth Hormone on Bone Density in CKD Children
The normal bone replacement process consists of two processes, namely bone formation and bone resorption.40 Growth hormone is one that affects the process of bone formation. Growth hormone directly and indirectly (via IGF-1) stimulates osteoblastogenesis and chondrogenesis.41 Osteoblasts play an important role in bone formation.
Osteoblasts are mononuclear cells that attach to the surface of bones and form new bone. The products produced by osteoblasts are called bone formation markers. Alkaline phosphatase (AP) is one of the markers of bone formation, which is an enzyme to prepare an alkaline atmosphere in the formed osteoid tissue, so that calcium can be easily deposited in that tissue.42,43 AP in serum comes from liver, bone, intestine, spleen, kidney and placenta. 42 During childhood and adolescence, bone-derived AP predominates and accounts for up to 90% of total serum AP. 44 In the absence of liver disease and liver enzyme results within normal limits, the increase in serum AP was considered to represent bone-specific AP.45 In this review of RCTs, three studies assessed serum AP and found a significant increase in serum AP in the growth hormone-treated group. 16,19,22
In addition to AP, osteocalcin is also a marker of bone formation. Osteocalcin plays an important role in bone, namely the process of mineralization and the process of calcium ion homeostasis. Osteocalcin
examination is a good parameter to determine disorders of bone metabolism during bone formation and bone replacement.45 Low osteocalcin is associated with an increased risk of fracture.42 Testing of osteocalcin is often used as a biomarker of bone-forming drugs and to assess the effectiveness of treatment outcomes. 45 In this review, there was a study that tested for osteocalcin and there was a significant increase in serum osteocalcin in the growth hormone-treated group. 22
5. Conclusion
Giving growth hormone is effective in improving the child's height PGK, and the dose should be given is 4 IU / m 2 / day, 1x daily, by subcutaneous injection and duration of administration varies depending on response to therapy. Administration of growth hormone does not aggravate kidney disorders in children with CKD.
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