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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 5  |  Page : 955-962
Serum osteoprotegerin (OPG) in children with primary nephrotic syndrome


1 Department of Pediatrics, Faculty of Medicine, Al-Minya University, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Al-Minya University, Egypt

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Date of Web Publication6-Sep-2011
 

   Abstract 

A novel cytokine system secreted by osteoblast, osteoprotegerin (OPG) and its ligand (OPGL) regulates osteoclastogenesis. To determine the relation of the serum OPG levels in children with nephrotic syndrome (NS) to the renal disease, we studied 30 patients with NS in comparison with 30 healthy children serving as controls. The study patients were divided into three equal groups: group 1 included newly diagnosed patients who were studied before and after a short course (one month) of steroid therapy for the first time, group 2 included frequent relapsers (FR), and group 3 included infrequent relapsers (IFR). In addition to serum OPG (ELISA), osteocalcin (OC), parathormone (PTH), alkaline phosphatase (ALP), and 24- hour urinary Ca and proteins were measured. The NS patients revealed a significantly lower serum OPG and parameters of bone formation (ALP and OC) and a significantly higher 24- hour urinary Ca than controls. A short course of glucocorticoids therapy for one month resulted in a significant decrease of serum OPG, ALP and OC levels and a significant increase of 24- hour urinary Ca, while serum PTH levels were not significantly affected by this the- rapy; the FR revealed a significantly lower serum level and a significantly higher 24- hour urinary Ca and serum PTH than the IFR. OPG had significant negative correlations with markers of disease activity and severity (ESR, serum cholesterol, 24- hour urinary protein and cumulative steroid dose), PTH and 24- hour urinary Ca. On the other hand, OPG had significant positive correlations with ALP, OC, and serum albumin. Low serum OPG, which is attributed to the renal disease and/or steroid therapy, may be an important factor contributing to bone resorption in NS. Studies of the protective effect of OPG administration against bone loss in NS are warranted.

How to cite this article:
Mohamed GB, Abdel-Latif EA. Serum osteoprotegerin (OPG) in children with primary nephrotic syndrome. Saudi J Kidney Dis Transpl 2011;22:955-62

How to cite this URL:
Mohamed GB, Abdel-Latif EA. Serum osteoprotegerin (OPG) in children with primary nephrotic syndrome. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2014 Oct 26];22:955-62. Available from: http://www.sjkdt.org/text.asp?2011/22/5/955/84395

   Introduction Top


Children with the nephrotic syndrome (NS) may be at risk for metabolic bone disease because of biochemical derangements caused by the renal disease as well as steroid therapy. [1],[2] Osteoporosis is a well known serious side- effect of long- term treatment with glucocorticoids (GC). However, the precise mechanism of this disorder is unclear. [3] Pharmacological doses of GC are associated with decreased gastrointestinal calcium (Ca) absorption and increased urinary Ca excretion, resulting in a negative calcium balance. Furthermore, GC stimulate bone resorption directly by enhancing osteoclast activity and indirectly via increasing parathormon (PTH) production in addition to suppression of type 1 collagen synthesis and decreasing of osteoblast differentiation with a resultant decrease of its products, including osteocalcin (OC), a major non- collagenous bone protein and an ideal marker of bone formation. Moreover, a drop in OC serum level may be an early marker for steroid- induced osteoporosis and avascular bone necrosis. [4],[5],[6]

The abnormal bone histology in NS patients cannot be readily explained by the prevalent concentrations of PTH and vitamin D metabolites. [7] Osteoprotegerin (OPG), a new cytokine system and a member of the tumor necrosis factor receptor superfamily, is secreted by osteoblasts and regulates osteoclastogenesis in addition to its ligand (OPGL) or receptor activator of nuclear factor- Kappa B ligand (RANKL). [8],[9],[10] OPGL is the final effector of osteoclastogenesis that promotes osteoclast formation (osteoclast differentiation factor) and activation, and inhibits osteoclast apoptosis. [11],[12] OPG blocks the biological effects of OPGL. [8] Thus, alterations in OPG/OPGL ratio could form the basis of some metabolic bone diseases such as osteoporosis. [13],[14]

Several studies have shown that PTH acts by enhancing the production of OPGL and by inhibiting the synthesis of OPG. [8],[15] Moreover, it has been proposed that GC administration results in suppression of serum OPG and over- expression of OPGL. This may be an important factor participating in GC- induced osteoporosis. [3]

Exogenous administration of OPG has been shown to increase bone mass and prevent bone loss. [16] Thus, OPG may represent a potential therapeutic target in pathological processes that are characterized by excessive bone resorption. [8]

The aim of this study is to measure the serum OPG levels in children with NS and determine its relation to the renal disease (activity and severity), steroid therapy (duration and cumulative dose), and PTH as well as markers of bone metabolism such as alkaline phosphatase (ALP) and OC as markers of bone formation and 24 hour urinary Ca as a marker of bone resorption.


   Subjects and Methods Top


We studied 30 children (19 males and 11 females) with NS recruited from the Pediatric Nephrology Clinic at the Pediatric Department of Suzan Moubarak Hospital of Al- Minya University from the 1 st of October 2006 to the end of July 2007. The diagnosis of NS was established according to the criteria of the International Study of Kidney Disease in Children. [17] Their ages ranged from 2 to 12 years, with a mean of 6.73 ± 2.7 years. The parents of the patients signed informed consents for the study.

Clinical evaluation of the patients was based on clinical history from the parents, reviewing follow- up sheets, and clinical examination. We emphasized the evaluation of the following data: disease duration, frequency of relapses, manifestations suggesting metabolic bone disease (bone pains, fractures, and deformity), and GC therapy (duration, response, side- effects, and the cumulative dose during the whole disease duration used per square meter body surface area obtained from the patients' records).

The patients were classified into three groups; group 1 included ten patients (seven males and three females) with a recent diagnosis of NS. They were studied before and after a short course of steroid therapy for the first time (60 mg/m 2 / day of prednisolone in three divided doses for one month). Their ages ranged from 2 to 9 years, with a mean of 5.9 ± 2.2 years.

Group 2 included ten patients (six males and four females) who were frequent relapsers (FR), i.e. with two or more relapses within six months of the initial response or four or more relapses within any 12- month period. [18] All the patients were steroid dependent, i.e. with two consecutive relapses occurring during or within 14 days of steroid cessation. [18] Their ages ranged from 4 to 12 years, with a mean of 7.4 ± 2.6 years. All the patients were studied during relapse (edema+, urinary protein excretion >40 mg/hour/m 2 or Albustix = ++ or more for three consecutive days). [18]

Group 3 included ten patients (six males and four females) who were infrequent relapsers (IFR) and steroid responsive, i.e. remission achieved with steroid therapy alone. [18] Their ages ranged from 4 to 9 years, with a mean of 6.4 ± 1.9 years. All the patients were studied during relapse.

The patients with NS were excluded from the study if they had impaired renal function (creatinine clearance <80 mL/min), secondary NS or if they were recipients of cytotoxic therapy or oral vitamin D (factors that may affect bone metabolism).

The patients were studied in comparison with 30 (19 males and 11 females) age- and sex- matched healthy children, with no clinical evidence of any disease or condition that may affect bone metabolism, serving as controls. Their ages ranged from 3 to 12 years, with a mean of 6.3 ± 3 years.

Specimen collection was done by venipuncture. Six milliliters of blood were collected. Four milliliters were transferred into a clean dry tube and left to clot. An aliquot of promptly separated serum was used for direct assay of urea, creatinine, Ca, phosphorus (P), ALP, cholesterol and albumin. Part of the serum was stored at - 20°C until assay of PTH (immunoradiometric assay), OC (radioimmunoassay) and OPG (ELISA). The other 2 mL were collected on sodium citrate for erythrocyte sedimentation rate (ESR) assay by Westergren method. A sample of 24- hour urine was used for measurement of urinary creatinine, total protein, and Ca levels; urine was collected in sterile containers with no preservatives and stored at 2-8°C till the time of the assay. The corrected creatinine clearance to the surface area was calculated for every study patient.


   Statistical Analysis Top


The collected data were analyzed using SPSS (Statistical Package for the Social Sciences). The mean and standard deviation (SD) were used to describe quantitative data. Student's "t" test was used to compare the parametric data of two groups. Pearson correlation was used to correlate two quantitative variables. For all tests, a probability, P, of less than 0.05 was considered significant.


   Results Top


Children with NS, whether in one group or classified into FR and IFR, had significantly lower serum OPG, ALP, and OC and significantly higher 24- hour urinary Ca levels than controls. Serum PTH was significantly higher in patients who were FR than in controls, but there was an insignificant difference between patients who were IFR and controls [Table 1], [Table 2] and [Table 3]. On the other hand, there was no significant difference in serum levels of Ca and P of the NS patients with those of the controls (P = 0.466 and P = 0.318).
Table 1: Comparison between the different studied groups in serum levels of OPG.

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Table 2: Comparison of serum levels of laboratory markers of bone formation (ALP and OC) between the different studied groups.

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Table 3: Comparison between different studied groups in serum levels of PTH and 24-hour urinary calcium (Ca).

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Newly diagnosed patients with NS, prior to GC therapy, had significantly lower serum OPG, ALP, and OC levels and significantly higher 24- hour urinary Ca levels than controls [Table 1], [Table 2] and [Table 3]. In contrast, there was an insignificant difference between the former group and the latter group in serum levels of Ca (P = 0.651), P (P = 0.171), and PTH [Table 3].

A short course of steroid therapy (60 mg/m 2 / day of prednisolone for one month) for the first time received by the newly diagnosed patients with NS resulted in a significant decrease of serum OPG, ALP, and OC levels and a significant increase of 24- hour urinary Ca levels [Table 1], [Table 2] and [Table 3]. In contrast, the - one month GC therapy did not seem to significantly affect the serum levels of Ca (P = 0.671), P (P = 0.262), or PTH [Table 3].

The patients with NS who were FR had received a significantly higher cumulative GC dose than the IFR (mean ± SD: 40815 ± 6525 vs 13680 ± 6637 mg/m 2 , respectively; P = 0.000). The former group had significantly lower serum OPG, ALP, and OC levels and significantly higher serum PTH and 24- hour urinary Ca levels than the latter group [Table 1], [Table 2] and [Table 3]. In contrast, there were insignificant differences between both groups in serum levels of Ca (P = 0.523) and P (P = 0.421).

OPG had significant negative correlations with the cumulative steroid dose, 24- hour urinary protein and Ca levels, ESR, serum cholesterol, and PTH, but had a significant positive correlation with serum albumin, ALP, and OC levels. On the other hand, it did not correlate significantly with either the age of the patients or the duration of the disease [Table 4].
Table 4: Correlation of serum OPG to different variables.

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   Discussion Top


In the present study, patients with NS, whether in one group or classified into newly diagnosed, FR, or IFR, had significantly lower serum OPG than controls. Our observed results were similar to other reports. [19] Our study revealed that GC therapy may be an important factor contributing to low serum OPG expression in NS. This was evidenced by the significant reduction of serum OPG in patients who were FR (with higher cumulative steroid dose) than those who were IFR (with lower cumulative steroid dose). In addition, OPG had a significant negative correlation with cumulative steroid dose, meaning that the higher the cumulative dose of GC received by these patients, the lower the serum OPG expression. It has been proposed that GC supports osteoclastic bone resorption by increasing the levels of RANKL and reducing OPG expression by direct suppression of osteoblast differentiation. Thus, GC increases the ratio of RANKL to OPG, resulting in promotion of osteoclastogenesis and bone loss. [3],[20],[21]

Another important reason behind OPG down- regulation in our patients with NS may be the renal disease itself. This was evidenced by the significant decrease of OPG in the newly diagnosed patients with NS prior to GC therapy as compared with controls. Another important clue is our finding of a significant negative correlation between OPG and markers of disease activity (ESR and serum cholesterol) and severity (24- hour urinary protein).

In our study, OPG had a significant negative correlation with the studied marker of bone resorption (24- hour urinary Ca), meaning that the lower the serum OPG levels, the higher is the degree of bone resorption, resulting in more urinary Ca excretion. Furthermore, OPG had a significant positive correlation with bone formation markers (ALP and OC). This could be explained in view of steroid- induced direct inhibition of osteoblast differentiation, [7] with a resultant decrease of its products (OPG, ALP, and OC).

The present study revealed a significant reduction of markers of bone formation (ALP and OC) and a significant increase of 24- hour urinary Ca (the studied marker of bone resorption) in all studied groups of patients than in controls. Few studies have been conducted for the evaluation of the magnitude and mechanism of osteopenia in children with NS, but results were conflicting. Similar to our findings are those of the study of Biyikli et al, [22] who reported enhancement of the bone resorptive markers and suppression of the bone formation markers in NS. However, in the study of Abu Al- Hassan et al, [23] conducted on Egyptian children with NS, osteopenia was associated with increased bone resorptive markers, while the bone formation markers were normal. These discrepancies may be attributed to variations in the number and age of the studied patients, duration of the disease, steroid dose and the methodology used to assess the laboratory markers of bone metabolism.

The significant decrease of markers of bone formation and the increase of the marker of bone resorption in our newly diagnosed patients with NS, prior to GC therapy, as compared with controls, may point to the significant role of the renal disease itself in the abnormality of bone metabolism in NS. Gulati et al [1] mentioned that biochemical derangements caused by the renal disease itself is one of the important leading causes of metabolic bone disease in NS. Other investigators reported that abnormalities of bone metabolism in NS occurred irrespective of steroid therapy as GC is not the only factor responsible for osteopenia. Other factors that may contribute to resorption include nutritional deficiency, hypoproteinemia, immobilization, [24] and proinflammatory cytokines excessively produced in active inflammation, which triggers excessive osteoclastic activity. [8]

In our study, patients who were FR had received a significantly higher cumulative steroid dose than those who were IFR. The former group had significantly lower parameters of bone formation and significantly higher 24- hour urinary Ca than the latter group. Osteoporosis is a well known serious side- effect of long- term treatment with GC. However, its precise mechanism is unclear. Pharmacologic doses of GC result in an increase of urinary Ca excretion due to stimulation of bone resorption directly by enhancing osteoclast activity and indirectly via increasing the production of PTH. Moreover, GC directly inhibit bone formation by decreasing osteoblast differentiation. [4] The latter assumption could explain the significantly lower OPG, ALP, and OC, which are osteoblast products, in steroid- treated patients with NS than controls.

A course of GC therapy for one month in our newly diagnosed patients with NS resulted in a significant reduction of OPG and markers of bone formation (ALP and OC) and a significant increase of 24- hour urinary Ca. This finding is comparable with the results of Sasaki et al, [3] who reported that a short course of GC to adult patients with different renal diseases had significantly suppressed serum OPG with concomitant enhancement of the bone resorptive markers and suppression of the bone formation markers. In contrast, there were negligible effects on PTH levels. They claimed that bone resorption after a short course of GC therapy had resulted from an inhibition of OPG rather than increment of PTH production.

In our study, the FR who received a high cumulative steroid dose had significantly higher PTH than the IFR with a low cumulative steroid dose. The former group had significantly higher serum PTH than controls, while the latter group and controls had comparable results of serum PTH. These findings denoted that prolonged course and high dose of GC therapy resulted in a significant increase of serum PTH levels. Contradictory to our results, other investigators [25],[26] reported normal serum PTH levels in children with steroid- dependent and frequently relapsing NS. These discrepancies may be attributed to variations in the duration of the disease and cumulative steroid dose. Further studies on a large scale are warranted to measure serum PTH expression in NS in relation to steroid therapy and frequency of relapses. In our study, PTH showed a significant negative correlation with OPG. Roux and Orcel [8] demonstrated that PTH upregulates RANKL and downregulates OPG expression in osteoblast/stromal cells, which is compatible with the results of our study.

Several lines of evidence indicate that the OPG/RANKL/RANK system plays a critical role in the development and function of the immune system. [27],[28],[29] Thus, the OPG/RANKL/RANK system may mediate important and complex links between the skeletal and immune systems. RANKL blockade (using OPG, RANK fusion proteins, or RANKL antibodies) has prevented bone loss caused by osteoporosis and chronic inflammatory disorders. [30] OPG is currently under investigation for osteoporosis treatment. [31],[32],[33]

We conclude that osteoporosis in NS could be attributed to both enhancement of bone resorption and suppression of bone formation. Low OPG, which could be attributed to both renal disease itself and steroid therapy, may be an important factor contributing to bone resorption in NS. Therefore, OPG administration may be considered as a new hopeful therapeutic agent for osteoporosis in NS, especially in patients who are FR and with high cumulative steroid dose. Further studies regarding the protective effect of OPG administration against bone loss in NS are warranted.

 
   References Top

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Correspondence Address:
Gamal B Mohamed
Department of Pediatrics, Faculty of Medicine, Al-Minya University
Egypt
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