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Revista chilena de pediatría

versión impresa ISSN 0370-4106

Rev. chil. pediatr. vol.88 no.1 Santiago  2017

http://dx.doi.org/10.1016/j.rchipe.2016.08.002 

Case Series

 

Somatropic axis and molecular markers of mineral metabolism in children undergoing chronic peritoneal dialysis

 

 

María Luisa Ceballos Osorio, Francisco Cano Schuffeneger

Pediatric Nephrology Unit, Luis Calvo Mackenna Hospital, Santiago de Chile, Chile

Correspondencia a:


Growth failure is one of the most relevant complications in children with chronic kidney disease (CKD). Among others, growth hormone (GH) resistance and bone mineral disorders have been identified as the most important causes of growth retardation. Objectives: 1. To characterize bone mineral metabolism and growth hormone bio-markers in CKD children treated with chronic peritoneal dialysis (PD). 2. To evaluate height change with rhGH treatment. Patients and Methods: A longitudinal 12-month follow-up in prepuberal PD children. Exclusion criteria: Tanner stage > 1, nephrotic syndrome, genetic disorders, steroids, intestinal absorption disorders, endocrine disturbances, treatment with GH to the entry of the study. Demographic and anthropometric data were registered. FGF23, Klotho, Vitamin D, IGF-1, IGFBP3, and GHBP were measured to evaluate mineral and growth metabolism. Results: 15 patients, 7 male, age 6.9 ± 3.0 y were included. Time on PD was 14.33 ± 12.26 months. Height/age Z score at month 1 was –1.69 ± 1.03. FGF23 and Klotho: 131.7 ± 279.4 y 125.9 ± 24.2 pg/ml, respectively. 8 patients were treated with GH during 6-12 months, showing a non-significant increase in height/age Z-score during the treatment period. Bivariate analysis showed a positive correlation between Klotho and delta ZH/A, and between GHBP vs growth velocity index (p < .05). Conclusions: FGF23 values were high and Klotho values were reduced in children with CKD in PD, comparing to healthy children. Somatotropic axis variables were normal or elevated. rhGH tends to improve height and there is a positive correlation of GHBP and growth velocity in these children.

Keywords: Peritoneal dialysis; Growth; GH; FGF23; Klotho.


 

Growth is a complex process that involves sequential changes in the morphology and function of cells. Particularly in bone growth, these changes occur in chondrocytes and osteocytes, therefore, any condition that blocks this process may cause bone deformities or a reduction in growth potential. Studies have shown that chronic kidney disease (CKD) and secondary hyperparathyroidism can significantly affect growth progression1.

Growth in childhood can be divided into 3 stages. During lactation, the phase of the fastest increase in height, dependent on nutrient intake, occurs. In mid-childhood, the growth rate remains constant at 5-7 cm/year, controlled by growth (GH) and thyroid hormones. Finally, during puberty, through the GH/ insulin-like growth factor1 axis, IGF1, and initiated by sex hormones, the puberty growth spurt is stimulated2, but delayed in CKD due to a pulsatile secretion loss of the hypothalamic gonadotrophin hormone (GnRH)2,3.

CKD is characterized by delayed growth not being able to reach the final adult size estimated by genetics4. According to data from the North American Pediatric Renal Trials and Collaborative Studies in 2011, 36.9% of children with CKD have a delayed growth, and the extent correlates with the deterioration of kidney function, with an average height of -1.85 SD. In Chile, according to the 2007 National Registry of the disease, 50% of patients with CKD have a delayed growth4.

The etiology of under height for age in CKD is multifactorial. Primary kidney disease, nutritional deficit, metabolic acidosis, hydroelectrolytic disorders, anemia, alterations of mineral metabolism, age at onset of CKD, chronic steroid treatments, and alterations of the GH/IGF1 axis are among the key associated factors3,5.

GH in CKD is found in either normal or increased values and its half-life is extended due to resistance to its action. The binding of GH to its receptor in tissues stimulates receptor dimerization and autophosphorylation of tyrosinkinases, Janus kinase 2, phosphorylating signal transducer and activator of transcription protein, STAT (1, 3 and 5). The phosphorylated STAT (STATp) are translocated to the nucleus, activating the gene expression regulated by GH1,2,6,7.

GH has an effect through IGF-1 produced in the liver. However, IGF-1 is also secreted locally in the growth plate, acting as a paracrine/autocrine factor6,7. In CKD, plasma IGF-1 levels may be normal or decreased, but its bioactivity is low6,7. This protein is carried through plasma by binding proteins, IGF -BPs (1 to 6), which prevent rapid metabolism. 99% of IGF-1 is bound to IGFBP-38 and to acid-labile subunit (ALS) 77, forming a ternary complex. In CKD, these IGF-BPs are increased due to a decreased clearance. On the other hand, the expression of the GH receptor in white cells and the banding protein GHBP are decreased2,3,5.

Recombinant GH (rhGH) is an effective and safe therapy for the treatment of short stature in CKD. However, despite its use, a final height close to -2 SD is still observed in all populations studied1.

According to an international consensus published in 20069, a treatment with rhGH should be considered in all patients with glomerular filtration rate < 75 ml/min/1.73 m2, in medical, dialytic treatment or kidney transplant recipients after one year of following, with a ZH/A score of <-1, 88 (<p3) or growth velocity (GV) SD <-27. The greatest effect on height is achieved at the first year of therapy, to decline thereafter10.

Chronic kidney disease (CKD) and secondary hyperparathyroidism can significantly affect bone growth. Alterations in mineral metabolism occur in the early stages of CKD and progress as kidney function deteriorates. These alterations are attributed to changes in the parathyroid hormone (PTH) and to the vitamin D axis that subsequently lead to disorders in the metabolism of calcium and phosphorus11. Fibroblast growth factor 23 (FGF23) is a key regulator12,13. FGF23 is synthesized by osteocytes of mineralized bone13, which under mechanical stress, generate transduction signals regulated by endocrine signals, modifying bone architecture and mineral homeostasis14. FGF23 reduces plasma phosphate levels, inducing phosphaturia and suppressing the synthesis of 1.25 OH-vitamin D15. In addition, it decreases the transcription and secretion of PTH16.

FGF23 requires Klotho, a single-pass transmembrane to cativate its receptor (FGF-Rs)14,17,18. Klotho deficiency has been described in CKD decreasing action of FGF19.

As FGF23 production occurs in osteocytes and its main renal feedback is 1.25 OH-vit D, it is important to know how this phosphatonin affects osteocyte metabolism and its impact on bone growth. The relationship among growth, GH-IGF1 axis and mineral metabolism markers, FGF23-Klotho, in children with CKD, has not been yet clarified.

The primary objective of this study was to characterize markers of mineral metabolism: FGF23-Klotho and the somatotropic axis: IGF1, IGFBP3 and GHBP in pediatric patients on chronic peritoneal dialysis (PD), and the secondary objective was to evaluate the change in height of patients treated with rhGH.

Patients and Method

Design

A prospective descriptive study in children with CKD on PD at the Pediatric Nephrology Unit of Luis Calvo Mackenna and Roberto del Río hospitals, with 12-month followed up.

Inclusion criteria

Newborn > 33 weeks gestational age, Tanner stage 1, stable biochemical parameters and informed consent. Stable patient was defined according to KDOQI guidelines20-22.

Exclusion criteria

Tanner ≥ 2; use of steroids, gastrointestinal malabsorption; endocrine diseases; genetic syndromes; active nephrotic syndrome; use of recombinant growth hormone at the start of the study; not consent to participation in the study.

The protocol was approved by the Ethics Commi­ttee of each hospital, the Ethics Committee of the Faculty of Medicine of Universidad de Chile and by the Ethics Committee of Fondecyt.

Variables evaluated

1. Demographic variables: age, sex, CKD etiology, age of onset of PD and time on PD.

2. Anthropometric variables: At the start of the study, at 6 and 12 months, based on Z-scores, the following information was registered: weight age (ZW/A) and height/age (ZH/ A), body mass index (ZBMI) and Growth velocity (GV). The weight was determined using a scale (Seca Corporation, Hamburg, Germany) with 0.1 kg accuracy and 150 kg maximum weight. Height was measured using a 1 mm precision stadiometer. At the time of enrollment, all patients had carpal radiography to estimate bone age (BA).

Patients were evaluated at the start and during the follow-up by a child nutritionist to ensure caloric and protein intake according to the K-DOQI 2008 nutrition guidelines22.

At follow-up at 6 and 12 months, there were two groups: treatment with rhGH (rGH +) and treatment without rhGH (rGH-).

To analyze the change in ZH/A during the 12-month follow-up in rGH + and rGH-, delta ZH/A (ZH/A month 12-ZT/A month one) was estimated for both chronological and bone age. GV (cm / year) was expressed as a categorical variable according to percentile (p) of GV curves published in 1985 by Tanner et al23. It was defined as category 1: GV> p10; Category 2: GV <p10 (short stature).

3. Biochemical variables: creatininemia (mg/dl) (isotope dilution mass spectrometry, IDMS, VITROS® 4600 Chemistry System), urea nitrogen (mg/dl), venous gases, plasma electrolytes, albumin, calcemia, phosphatemia, hemoglobin, hematocrit, ferritin, and intact PTH (immunoradiometric assay, CMIA, Immunotopics, San Clemente, CA) were obtained monthly through blood samples.

4. Variables of mineral metabolism: at the start of the protocol, levels of 25 (OH) vit D3 and 1.25 (OH) vit D3 (RIA), FGF23 (pg/ml, ELISA two sites, Immunotopics, San Clemente, CA) and Klotho (pg/ml, ELISA, Cusabio, China) were identified. The levels of FGF23 and Klotho were also determinated at months 6 and 12 of the follow-up.

5. Somatropic axis variables: GHBP (ELISA kit CSB-E09149 h, Gentaur, detection range: 10 to 200 ng/mL), IGF-1 (ng/mL, RIA) and IGFBP-3 (mg/mL, IRMA) were identified in the plasma.

6. Dialytic variables: all children were treated with automated peritoneal dialysis using the Baxter Home Choice PD System, with an exchange volume of 1.100 ml/m2 and dextrose concentrations of 1.5-4.25% of Dianeal® solutions according to the specific requirements of each patient. A total urea Kt/V of 2.1 was considered.

Statistical Analysis

Variables of normal distribution are expressed in averages and standard deviations. Those with non-normal distribution are expressed in medians and ranges. Differences among normal distribution groups were evaluating by the t test, and those with non-normal distribution by the Wilcoxon sign-rank test. Pearson’s correlation coefficient was used to determine the association among the variables. p < 0,05 was considered significant. Data were analyzed using the SPSS program (SPSS Inc, Chicago, USA).

Results

Fifteen patients aged 6.9 ± 3.0 years old (7 males) were enrolled. The age of onset of PD was 6.4 ± 3.7 years old, time in PD: 14.3 ± 12.3 months. Etiologies of CKD were kidney dysplasia in 6 patients, obstructive uropathy in 2, hereditary nephropathies in one, hemolytic uremic syndrome in 3, vasculitis in one and unknown in 2 patients.

Bone age in children on PD was delayed compared to chronological age (5.6 ± 2.9 versus 6.9 ± 3.0 years). Biochemical and mineral metabolic variables at the starting month in the study are shown in table 1. No significant differences in the variables were observed during the 12-month follow-up.

Table 1. Biochemical and mineral metabolism variables in 15 CKD PD patients, during 12 month follow-up

Biochemical parameters of the somatotropic axis at month one were expressed as a Z score for chronological age and adjusted for bone age. Z IGF-1: 0.72 ± 3.53 and Z IGF-1 BA 2.72 ± 4.88, and Z IGFBP-3 1.35 ± 1.63 and Z IGFBP-3 BA 2.32 ± 2, 15, respectively24. Quantification of GHBP resulted in an average value of 30.8 ± 35.8 ng/ml.

Anthropometric data at the start and end of the follow-up are shown in table 2. A ZW/A score of -1.41 ± 1, 11, ZH/A -1.69 ± 1.03, and Z BMI of -0.36 ± 1.14 was observed at admission. After adjusting the ZH/A score by bone age, the value was -0.12 ± 1.81. Table 2 also shows the anthropometric characteristics differentiating patients according to the use of rGH. An increase in the number of children receiving this therapy throughout the study period was observed, with 7/14 patients at month 6 and 8/12 at month 12. ZH/A score in the rGH + group did not show significant differences during the follow-up period (-1.7 ± 1.17 vs -1.41 ± 0.84, p = ns). After adjusting the Z H/A BA score there were also no significant differences. In rGH + and rGH- patients, both groups had similar mineral and somatotropic axis metabolic markers, except for PTH at month 6, which was found to be significantly higher in rGH- children (p = 0.035) (table 3).

Table 2. Anthropometric variables in 15 CKD PD patients, during 12 month follow-up

Table 3. Characterization PD patients with or without rGh therapy, during 12 month follow-up

Delta ZH/A (ZH/A month 12-ZH/A month one) for both chronological age and corrected bone age, showed no significant differences between rGH + and rGH- groups during the analyzed period (figures 1 and 2). At six-month follow-up, the GR of 7 rGH + patients was as follows: 5 in GR category 2 (short stature) and 2 in category 1; same scenario when adjusted by GR BA. At month 12, out of the 8 rGH + patients: only 2 were in category 2 and 3 grew below p10 when adjusted by GR BA.

Figure 1. Delta Z H/A month 12 and 1 in CKD PD patients (p= 0.407).

Figure 2. Delta Z H/A BA month 12 and 1 in CKD PD patients (p= 0.407).

A positive correlation was observed between BMI at month 12 and delta ZH/A (p = 0.015, coefficient of Pearson correlation: 0.68) and between Klotho and delta ZH/A BA levels (p = 0.045, Pearson correlation coefficient: 0.725) during the bivariated analysis. GHBP showed a negative correlation with chronological age, bone age, weight, height and BMI, and a positive one with GR (p = 0.002, correlation coefficient = 0.78) (figure 3).

Figure 3. GHBP and Height velocity in CKD PD patients.

The loss of patients during the study occurred at month 6 due to: kidney transplant from a living donor; and at month 12: 2 children due to kidney transplant from a deceased donor and another due to transfer to hemodialysis.

Discussion

Growth retardation remains a major problem in children with CKD. Despite advances in medical management and kidney replacement therapies, 30-60% of children have short stature in adulthood25.

In this study, children on stable PD (according to K-DOQI guidelines) showed a significant height deficit, therefore, it is important to know the pathophysiological mechanisms that lead to this disorder.

Secondary hyperparathyroidism of CKD interferes with longitudinal growth, leading to destruction of growth plate. However, slight elevations of PTH are considered necessary to stimulate the expression of vitamin D receptors in growth plate and local synthesis of IGF-126. The discovery of the FGF23 and their cofactor Klotho represents an important advance to understand this pathology. FGF23 decreases phosphate reabsorption in the proximal tubule by reducing the expression of sodium-phosphate cotransporter 2a (NaPi-2a) in the apical membrane, generating phosphaturia and suppressing the Cyp27b1 gene encoding 1 a-hydroxylase enzyme, responsible for the second hydroxylation and activation of 25 (OH) vit D3. Also increase expression of Cup 24 gene enconding 24-hydroxilase enzyme, that cause vitamin D suppression27,28. In a previous study of the research team as well as in the patients of this study, FGF23 values ​​in children with CKD on PD were found to be significantly higher than the mean value observed in the control group of healthy children. The Klotho cofactor analysis showed lower values than the control group, and no association with FGF23 or with other biochemical variables studied were found28. Sugiura et al., measured the expression of soluble Klotho using an ELISA kit in patients with CKD and in controls, confirming that this protein has decreased levels in uremic patients29.

Wesseling-Perry et al., reported results in 52 patients with grade 2-4 CKD, aged between 2 and 21 years. Plasma FGF23 levels were related to bone mineralization defects, suggesting that this hormone could be associated with height retardation in children with CKD30. In this study, the bivariate analysis did not confirm these results and only showed a significant correlation between Klotho levels and delta Z H/A BA, something that should be verified with other studies and whose possible association need further analysis.

The IGF network is composed of 2 types of ligands: cell surface membrane receptors and 6 soluble binding proteins, IGF-BP. This is fundamental for embryonic and postnatal growth and plays an important role in immune system function, lymphopoiesis, myogenesis and bone growth. The binding of IGF to its receptor, IGF-1R, activates intrinsic protein tyrosine-kinase activity, resulting in intracellular signals that regulate various biological responses8.

Osteocytes are the biggest cell subtype at bone level (90-95% of bone cells). Their star shape and dendritic projections allow close intercellular exchange with the pericellular matrix, converting mechanical stimuli into biochemical and electromechanical signals. These cells respond to hormonal stimuli such as: PTH, 1.25 (OH) vit D3, calcitonin, glucocorticoids, estrogens and testosterone, and have their own endocrine properties synthetizing sclerostin, matrix extracellular phosphoglycoproteins (PHEX, DMP1 , MEPE), FGF-23, etc., among others14.

IGF-1 is synthesized in the liver and locally in the growth plate. It circulates in the blood along with IGFBP and ALS. In CKD, IGFBP has been reported to be 1.5 times higher than IGF-1, reducing the biologically active free IGF-12. It has recently been reported that local bone production of IGF-1 by osteocytes, osteoblasts and chondrocytes has been observed. Therefore, the local IGF-1 production is involved in bone turnover, modeling, and remodeling. Transgenic mice studies with conditional knockout of Igf1 in osteocytes show a malfunction of postnatal periosteal longitudinal and bone growth, whereas a reduction of hepatic IGF-1 of more than 75% does not have a significant impact on growth31. This may partly explain the results of this study, since although children on PD have adequate levels of IGF-1, they have a significant stature retardation.

Somatotropic axis disorders in children with CKD occur at different levels of the signal pathway. GH levels vary considerably at different stages of development. In the prepubertal stage, its secretion is either normal or increased through a decrease of feedback of IGF-1, but during puberty, GH decreases by inhibition mediated by sex hormones. GHBP and the GH receptor are decreased and at the post-receptor level, there are defects in the JAK2/STAT signals32,33.

Studies in children with CKD have demonstrated normal or increased baseline levels of GH, therefore, a resistance to growth hormone2. Some of the mechanisms that explain this phenomenon include: decreased expression of the GH receptor gene34,35, decreased IGF-1 gene expression35, increased binding of IGF-1 to transport proteins36 and post-receptor defects of IGF- 137. Our biochemical parameters of somatotropic axis at month one, revealed that IGF-1 is in the normal-high range, although with a great deviation. As for IGFBP-3, it is increased as described by other authors.

GHBP is produced by the proteolytic cleavage of the GH receptor, releasing the extracellular domain into circulation. This is why some authors consider GHBP as a marker of GH receptor abundance in tissues38. However, there is great controversy regarding the interpretation of the values ​​found6,39,40. In our study, a great variation in GHBP levels was observed, similar to that reported by Toenshoff, assuming a non-normal distribution. In addition, GHBP values ​​correlated with BMI (expressed in SD) and proved to be the best predictor of GV in the cohort of patients studied41.

We observed a significant correlation between GHBP levels and GV in our patients, but not with the other growth parameters or BMI. However, the patients of the studies discussed were in the predialysis phase and the method of measurement of GHBP was based on an assay on an immune-functional ligand vs. the enzymatic assay used in our study41.

Our research group published an in vitro study of intracellular GH axis in children with CKD. The results showed a significant decreased JAK-2 phosphorylation and a decreased STAT-5b translocation to the nucleus, resulting in a decreased expression of target proteins such as IGFBP342. These defects are consistent with Schaefer et al findings in experimental models in uremic rats, observing a decreased phosphorylation of JAK-2 and STAT-5; decreased translocation of phosphorylated STAT proteins to the nucleus and increased SOCS inhibitory proteins compared to healthy rats43.

RhGH treatment has shown to significantly improve stature in these patients, with an increase of 0.73 SD in children under 5 years old and 0.26 SD in those older than 6 years old, after a year of treatment4,7; however, this treatment does not completely reverse the growth deficit, resulting in a final stature shorter than the expected by genetics. This was corroborated in our study, as the children treated with rhGH did not present a significant increase of the Z H/A score. This could have been influenced by the duration of therapy (less than one year) and the genetic potential of the parents, something not considered in the analysis of our results.

All the above shows that growth retardation in children with CKD is even more complex than what is known so far, and understanding the mechanisms that determine growth will allow new therapies under study such as recombinant IGF-1, recombinant IGFBP3 and IGFBP blockers can improve GH resistance to better manage these patients.

 

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__________________

Ethical Responsibilities

Protection of People and animals: The authors reported that no experiments on either people or animals have been performed.

Confidentiality of personal data: The authors reported that no patient data is contained in this article.

Privacy Right and informed consent: The authors have obtained the informed consent from patients and/or subjects referred to in the article. These documents are in the possession of the corresponding author.

Funding

Funded by Fondecyt 1110226.

Conflict of interests

The authors declare no conflict of interest.

Received: 16-2-2016; Accepted: 1-8-2016

Correspondencia a:

María Luisa Ceballos Osorio

maluceballos12@gmail.com - maluceballos@yahoo.es

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