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IGFs and IGF-binding proteins in short children with steroid-dependent nephrotic syndrome on chronic glucocorticoids:
1Department of Medicine, National University of Singapore, Singapore 119074.
Insights
Children with steroid-dependent nephrotic syndrome (SDNS) experience growth retardation due to IGF-I resistance, despite remission. Growth hormone (GH) treatment effectively increases IGF-I levels, overcoming this resistance and improving growth in these patients.
Area of Science:
- Pediatric Endocrinology
- Nephrology
- Growth Hormone Therapy
Background:
- Children with steroid-dependent nephrotic syndrome (SDNS) often exhibit growth retardation and short stature, even when in remission with glucocorticoids.
- The underlying mechanisms for growth impairment in SDNS are not fully understood, with potential contributions from both chronic glucocorticosteroid use and the nephrotic syndrome itself.
Purpose of the Study:
- To investigate alterations in Insulin-like Growth Factors (IGFs) and IGF-Binding Proteins (IGFBPs) in short children with SDNS.
- To prospectively evaluate the effects of 1 year of growth hormone (GH) treatment on these growth factors in SDNS patients.
Main Methods:
- Studied serum total and free IGF-I, IGFBP-3, and acid-labile subunit (ALS) in eight SDNS boys before, during, and after 1 year of GH treatment.
- Compared pretreatment levels with bone age-matched and chronological age-matched control groups.
- Monitored serum and urinary IGFBPs monthly using Western ligand blot and immunoblot techniques.
Main Results:
- Pretreatment, SDNS children showed elevated serum total IGF-I and IGF-I/IGFBP-3 ratio, with significantly higher free IGF-I compared to controls.
- Urinary IGFBP-2, IGFBP-3, and ALS were uniquely detected in SDNS children.
- GH treatment significantly increased serum IGF-I and IGFBP-3, which returned to baseline post-treatment; urinary IGFBPs remained unchanged.
Conclusions:
- Children with SDNS in remission exhibit persistent urinary loss of IGFBP-2, IGFBP-3, and ALS.
- Glucocorticoid-induced insulin-like growth factor (IGF) resistance is the primary driver of growth retardation in these children.
- Exogenous GH effectively overcomes IGF resistance by further elevating serum IGF-I levels.
Objective:
Children with steroid-dependent nephrotic syndrome (SDNS), despite being in remission on glucocorticoids, continue to have growth retardation and short stature. The mechanism is uncertain as both chronic glucocorticosteroids and the nephrotic syndrome may independently affect growth. We investigated the changes in the IGFs and IGF-binding proteins (IGFBPs) in a group of short SDNS children, and studied the changes prospectively with 1 year's treatment with GH.
Design And Methods:
Total and 'free' IGF-I, IGFBP-3 and acid-labile subunit (ALS) were studied in eight SDNS boys (mean age=12.6 years; mean bone age=9.1 years) on long term oral prednisolone (mean dose 0.46 mg/kg per day) before, during, and after, 1 year's treatment with GH (mean dose 0.32 mg/kg per week). Pretreatment comparisons were made with two control groups, one matched for bone age (CBA; mean bone age=9.2 years), and another for chronological age (CCA; mean chronological age=13 years). Subsequently, three monthly measurements of serum and urine IGFBPs were carried out in the GH-treated SDNS patients using Western ligand blot and Western immunoblot.
Results:
Pre-treatment serum total IGF-I levels and the IGF-I/IGFBP-3 ratio were elevated significantly in SDNS compared with CBA, and were similar to CCA. Serum free IGF-I levels were elevated significantly compared with both control groups, but serum IGFBP-3 did not differ significantly. Urinary IGFBP-2, IGFBP-3 and ALS were detectable in the SDNS children only. With GH treatment, IGF-I and IGFBP-3, but not IGF-II, increased significantly compared with pre-treatment values, and returned to baseline after cessation of GH treatment. Urinary IGFBPs did not change significantly with GH treatment.
Conclusions:
There is persistent urinary loss of IGFBP-2, IGFBP-3 and ALS in children with SDNS in remission with growth retardation. However, the significant elevation in serum IGF-I suggests that glucocorticoid-induced resistance to IGF is the main factor responsible for the persistent growth retardation in these children. Exogenous GH was able to overcome this resistance by further increasing serum IGF-I.