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Effects of Chronic Renal Failure and Growth Hormone on Serum Levels of Insulin-Like Growth Factor-Binding Protein-4 (IGFBP-4) and IGFBP-5 in Children: A Report of the Southwest Pediatric Nephrology Study Group^1,2

Baylor College of Medicine (D.R.P., S.K.D., E.D.B.), Houston, Texas 77030; Genentech, Inc. (J.W.F.), South San Francisco, California 94080; University of Washington (S.L.W.), Seattle, Washington 98108; Columbia Hospital at Medical City (R.J.H.), Dallas, Texas 75230; and Loma Linda University and Jerry L. Pettis Veterans Administration Medical Center (S.M.), Loma Linda, California 92357

Address all correspondence and requests for reprints to: Dr. David R. Powell, Texas Children’s Hospital, Feigin Center, MC# 3–2482, 6621 Fannin, Houston, Texas 77030. E-mail: dpowell{at}bcm.tmc.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Children with chronic renal failure (CRF) have high serum levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), -2, and -6. The excess IGFBP-2 and -1 may play a role in the growth failure of CRF children by sequestering IGF peptides. In contrast, IGFBP-3 levels rise with GH treatment of CRF children, suggesting a role for IGFBP-3 in their accelerated growth. The present studies used sensitive and specific antisera to characterize levels and forms of IGFBP-4 and -5 in serum from CRF children. By RIA, the mean baseline serum level of IGFBP-4 was high in CRF children compared to that in normal children, but the IGFBP-4 level in CRF serum did not correlate with height SD score; by immunoblot, high CRF levels were associated with increases in both intact and fragmented IGFBP-4. Mean RIA levels of IGFBP-5 were comparable in sera from CRF and normal children. Treating CRF children with GH for 12 months increased serum IGFBP-4 levels by 26% and IGFBP-5 levels by 49%, as determined by RIA; levels of IGFBP-5, but not IGFBP-4, correlated significantly with serum levels of IGF-I, IGF-II, IGFBP-3, and acid-labile subunit and with growth rate in these GH-treated children. In summary, IGFBP-4 levels are high in serum of CRF children, and GH increases serum levels of IGFBP-4 and IGFBP-5 in these children. The data suggest a role for IGFBP-5 in the accelerated growth of GH-treated CRF children, perhaps as part of a ternary complex with acid-labile subunit and IGFs. Additional studies on the relationship between intact IGFBP-4 levels and growth are needed to determine what role IGFBP-4 plays in the linear growth process in vivo.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
CHILDREN with chronic renal failure (CRF) often fail to achieve adult height consistent with their genetic potential despite aggressive supportive care (1, 2). The GH/insulin-like growth factor (IGF)/growth plate chondrocyte axis plays a major role in linear growth, and many abnormalities of this axis exist in serum of CRF children (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15). A key finding is the decreased ability of CRF serum to stimulate IGF mitogenic and metabolic pathways in chondrocytes despite normal or high levels of GH, IGF-I, and IGF-II (3, 4, 5, 6, 7). This decreased IGF bioactivity is due to excess serum IGF-binding proteins (IGFBPs) that belong to a family of six proteins that bind IGFs with high affinity (7, 8, 16, 17). Current in vitro and in vivo evidence suggests that excess intact IGFBPs can impair linear growth (18, 19, 20, 21). In the serum of growth-retarded CRF children, levels of intact IGFBP-1 and -2 are high and correlate significantly and negatively with the height SD score (11, 12), suggesting a role for intact IGFBPs in the growth failure of CRF children.

IGFBP-3 levels are high in CRF serum due to an excess of IGFBP-3 fragments with low IGF affinity (7, 8, 22, 23). Before GH treatment, IGFBP-3 levels do not correlate significantly with the height SD score of growth-retarded CRF children (12). However, GH induces a rise in IGFBP-3 levels in CRF serum that correlates significantly and positively with increases in height SD score and in serum levels of IGF-I, IGF-II, and acid-labile subunit (ALS) (12). This suggests that serum IGFBP-3 participates in the GH-induced catch-up growth of these children, perhaps by releasing IGFs to target tissues such as growth plate chondrocytes.

IGFBP-4 is a well known inhibitor of IGF action on cartilage (24) and cultured cells (25, 26, 27). IGFBP-5, identified in medium conditioned by bone cells and in human bone matrix, potentiates IGF actions in osteoblasts (27, 28, 29, 30) and either potentiates (31) or inhibits (32) IGF action in other cell types depending on experimental conditions. These observations suggest that IGFBP-4 and IGFBP-5 may play roles in the growth of CRF children. To evaluate this possibility, we used recently developed antisera to characterize levels and forms of IGFBP-4 and IGFBP-5 in serum from growth-retarded CRF children before and during GH therapy.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Experimental subjects and study design

Sera were obtained from 44 children with CRF who did not yet require dialysis [glomerular filtration rate (GFR) between 10–40 mL/min·1.73 m²] and who were part of an open label, multicenter trial of the effects of recombinant human GH on CRF children. Of the 44 children, 30 were randomized to the GH treatment group, and 14 were randomized to the untreated group. The study design, approved by the institutional review board for research involving human subjects of each participating center, has been described (12). Characteristics of the GH-treated and untreated groups at baseline and during the first year of study, including GFR, anthropometrics, and serum levels of IGF-I, free IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-6, ALS, insulin, GH-binding protein, and PTH have also been described (12, 14). Control sera were obtained from 10 healthy prepubertal children (12, 14). Blood samples were centrifuged, and the sera were frozen (-80 C) until assay.

Serum protein assays

IGFBP-4 RIA. IGFBP-4 was measured by RIA using guinea pig antiserum raised against recombinant human IGFBP-4 (rhIGFBP-4) expressed in Escherichia coli as reported previously (33); this antiserum has no significant cross-reactivity with other IGFBPs (33, 34). The same rhIGFBP-4 served as standard and radioactive trace.

IGFBP-5 RIA. IGFBP-5 was measured by RIA using guinea pig antiserum raised against rhIGFBP-5 expressed in E. coli as reported previously (35); this antiserum has no significant cross-reactivity with other IGFBPs (35, 36). The same rhIGFBP-5 served as standard and radioactive trace.

Immunoblotting

Serum (20 µL) diluted with 30 µL H₂O and 50 µL nonreducing dissociation buffer (0.125 mol/L Tris HCl, pH 6.8; 20% glycerol; and 4% SDS) was subjected to SDS-PAGE overnight at 10 mA through a 10–20% gradient gel. Proteins were transfered to a 0.45-µm pore size BA-S nitrocellulose membrane (Schleicher & Schuell, Inc., Keene, NH) as previously described (35). Nitrocellulose membranes were blocked for 1 h with 5% nonfat dry milk, incubated for 1 h with antiserum to IGFBP-4 (1:1000 dilution) or IGFBP-5 (1:200 dilution), and then incubated for 1 h with horseradish peroxidase-conjugated rabbit antiguinea pig IgG (1:1000 dilution; Zymed Laboratories, San Francisco, CA). Antigen-antibody reactions were visualized using ECL chemiluminescence reagents as recommended by the manufacturer (Amersham Life Sciences, Arlington Heights, IL).

Statistics

Data, presented as the mean ± SD, were converted to log₁₀ values for statistical analysis. Differences within untreated and GH-treated CRF groups at 3 and 12 months, between these two groups at baseline, and between all CRF children and normal children at baseline were evaluated for significance by Student’s t test. Differences between untreated and GH-treated CRF groups at 3 and 12 months were evaluated for significance by analysis of covariance using the baseline level as covariate. For all comparisons, differences were considered significant when P 0.05. When correlating variables measured at baseline in all CRF children, Pearson correlation coefficients were calculated. When correlating variables measured in GH-treated CRF children during the treatment phase of the study, Pearson correlation coefficients were calculated using the mean of the 3 and 12 month values for each variable.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Serum IGFBP-4 levels at baseline

By RIA, the mean serum IGFBP-4 level of 39.4 ± 9.9 nmol/L in the 44 CRF children was significantly higher than that of 10.6 ± 2.9 nmol/L in the 10 normal children (P < 0.001). Immunoblots performed with the same IGFBP-4 antiserum suggest that increases in both intact and fragmented IGFBP-4 contribute to the rise in IGFBP-4 levels in CRF serum (Fig. 1).

View larger version (72K): [in this window] [in a new window]   Figure 1. Immunoblot of IGFBP-4 in CRF and normal sera at baseline. Sera from two CRF children and two normal children were separated by SDS-PAGE, transfered to nitrocellulose, and then immunoblotted with IGFBP-4 antiserum. The molecular masses, in kilodaltons, of markers are shown on the left.

Serum IGFBP-5 levels at baseline

By RIA, the mean serum IGFBP-5 level of 8.0 ± 2.6 nmol/L in the 44 CRF children was not significantly different from that of 9.4 ± 2.5 nmol/L in the 10 normal children. Immunoblots performed with the same IGFBP-5 antiserum suggest that the majority of IGFBP-5 in CRF serum is fragmented (Fig. 2).

View larger version (42K): [in this window] [in a new window]   Figure 2. Immunoblot of IGFBP-5 in CRF sera before and after GH treatment. Sera obtained from CRF children (subjects 1 and 2) before and after they received 12 months of GH treatment were separated by SDS-PAGE, transfered to nitrocellulose, and then immunoblotted with IGFBP-5 antiserum. The molecular masses, in kilodaltons, of markers are shown on the left. The locations of intact IGFBP-5 and IGFBP-5 fragments are shown on the right.

View larger version (28K): [in this window] [in a new window]   Figure 3. Correlation between serum levels of IGFBP-5 and other IGF axis proteins at baseline in CRF children. In the 44 CRF children, serum IGFBP-5 levels at baseline were correlated with baseline serum levels of IGF-I (A), IGF-II (B), IGFBP-3 (C), ALS (D), IGFBP-1 (E), and IGFBP-2 (F). All levels were converted to log10 values before analysis.

IGFBP-4 levels rose slightly but significantly in the serum of CRF children after 3 and 12 months of GH treatment (Fig. 4A). GH did not alter the relative abundance of intact vs. fragmented IGFBP-4 (data not shown). The mean serum IGFBP-4 levels measured after 3 and 12 months of GH treatment in 30 CRF children correlated significantly and negatively with GFR (r = -0.51; P = 0.006), but did not correlate with the GH-induced change in height SD score. During GH treatment, serum IGFBP-4 levels did not correlate significantly with IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3, or ALS levels.

View larger version (16K): [in this window] [in a new window]   Figure 4. Effect of GH treatment on serum levels of IGFBP-4 and IGFBP-5 in CRF children. Thirty CRF children were treated with GH, and 14 CRF children served as untreated controls (No Rx). Sera drawn at baseline (0) or after 3 months (3 ) or 12 months (12 ) of study from each child were assayed by IGFBP-4 RIA (A) or IGFBP-5 RIA (B). Values represent the mean ± SD. 1) Different from 0 month GH values, P = 0.008; 2) different from 0 month GH values, P = 0.005; 3) different from 12 month No Rx values, P = 0.0003; 4) different from 0 month GH values, P < 0.0001; 5) different from 3 month No Rx values, P = 0.0002; 6) different from 12 month No Rx values, P < 0.0001.

GH significantly increased IGFBP-5 levels in the serum of children with CRF (Fig. 4B). In the 30 CRF children treated with GH, IGFBP-5 levels rose from 8.3 ± 2.8 nmol/L at 0 months to 11.6 ± 4.2 nmol/L after 3 months of treatment and 12.3 ± 3.2 nmol/L after 12 months of treatment. In contrast, serum IGFBP-5 levels in untreated CRF children at 0 months (7.5 ± 2.2 nmol/L) and 12 months (7.7 ± 1.5 nmol/L) of study were not significantly different. By immunoblot, GH did not clearly alter the relative amounts of intact vs. fragmented IGFBP-5 in sera of CRF children (Fig. 2).

The mean serum IGFBP-5 levels measured after 3 and 12 months of GH treatment in 30 CRF children correlated significantly and positively with the improved height SD score of these children after 12 months of GH; positively with the mean of 3 and 12 month levels of serum IGF-I, IGF-II, IGFBP-3, and ALS; and negatively with the mean of 3 and 12 month levels of serum IGFBP-1 and IGFBP-2 (Table 1).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

PTH stimulates IGFBP-4 production by bone cells and correlates positively with serum IGFBP-4 levels in normal individuals (33, 38), but the absence of a significant correlation between PTH and IGFBP-4 levels in the present study suggests that PTH is not responsible for high IGFBP-4 levels in CRF sera. The significant negative correlation between serum IGFBP-4 levels and GFR suggests that intact and fragmented IGFBP-4 accumulate in CRF serum due to decreased renal clearance rather than increased production.

At baseline, serum IGFBP-5 levels correlated positively and significantly with serum levels of IGF-I, free IGF-I, IGF-II, IGFBP-3, and ALS, all of which are up-regulated by GH (9, 12, 39, 40, 41). This suggests that IGFBP-5 is a GH-responsive protein, consistent with the 15% increase in IGFBP-5 levels noted in the serum of GH-deficient children after 12 months of GH treatment (36). In the present study, GH increased serum IGFBP-5 levels by 40% and 49% after 3 and 12 months of treatment, respectively, and the increased IGFBP-5 levels correlated significantly with the increased levels of IGFs, IGFBP-3, and ALS measured at 3 and 12 months. These observations provide strong evidence that IGFBP-5 is a GH-responsive protein in vivo.

In serum, IGFBP-3 and IGF levels correlate positively and strongly with ALS levels, probably because ALS greatly prolongs the half-life of IGFs and IGFBP-3 by associating with these proteins in a stable IGFBP-3/IGF/ALS ternary complex (42). The correlation of IGFBP-5 levels with levels of ALS, IGFs, and IGFBP-3 suggests that IGFBP-5, like IGFBP-3, forms a ternary complex with an IGF and an ALS protein. This is consistent with recent data indicating that IGFBP-5 circulates primarily in IGFBP-5/IGF/ALS ternary complexes in human serum (43) and with the fact that IGFBP-3 and -5 share a homologous 18-amino acid basic domain that allows IGFBP-3 to bind ALS (44).

The GH-induced rises in serum IGF-I, IGF-II, IGFBP-3, and ALS levels in CRF children each correlate positively with improved linear growth, suggesting that these proteins may promote growth in CRF children, probably as part of the IGFBP-3/IGF/ALS ternary complex (12, 15). The observations that serum IGFBP-5 levels in GH-treated CRF children correlate positively with improved linear growth; positively with serum levels of IGFBP-3, IGFs, and ALS; and negatively with serum levels of IGFBP-1 and -2, which are likely to be growth inhibitors in CRF (12, 13), all suggest that IGFBP-5 is more likely to stimulate than inhibit the growth of CRF children. IGFBP-3 can stimulate anabolic pathways by releasing IGFs to target tissues after proteolysis lowers IGFBP-3 affinity for IGFs. This may be how IGFBP-3 promotes growth in CRF, as most IGFBP-3 in the ternary complex of CRF serum is a 29-kDa fragment with low IGF affinity (7, 15, 23). IGFBP-5, also found in CRF serum mainly as IGFBP-5 fragments, may promote growth by this same mechanism. Alternatively, IGFBP-5 fragments may directly stimulate cell growth in the absence of IGFs (30).

In CRF children, IGFBP-4 levels rose approximately 26% after 12 months of GH treatment, but did not correlate significantly with levels of IGF-I, IGF-II, IGFBP-3, IGFBP-5, or ALS either before or during GH treatment. This suggests that serum IGFBP-4/IGF/ALS ternary complexes do not form, consistent with the recent data of Twigg and Baxter (43). At present, it is unclear whether this slight rise in serum IGFBP-4 levels participates in the improved growth of GH-treated CRF children. However, the delayed embryonic growth of mice lacking an IGFBP-4 gene suggests that under certain circumstances, IGFBP-4 may be a growth stimulator (45).

Thus, the present data show that IGFBP-4 and IGFBP-5 are GH-responsive proteins. The data also suggest that IGFBP-5 forms a ternary complex in serum and may act as a growth enhancer in CRF children. Future studies will determine what, if any, role IGFBP-4 plays in the linear growth process in vivo.

	Footnotes

 
¹ This work was supported by NIH Grants RO1-DK-38773 (to D.R.P.) and AR-31062 (to S.M.), a grant from Genentech, Inc. (South San Francisco, CA), and Grant M01-RR-00069 from the General Clinical Research Centers Program, National Centers for Research Resources, NIH.

² Southwest Pediatric Nephrology Study Group Centers/Participants: Baylor College of Medicine (Houston, TX): David Powell, M.D., Eileen Brewer, M.D., Andrea Forbes, R.N., and Evelyn Janoff, R.N.; Arkansas Children’s Hospital (Little Rock, AR): Eileen Ellis, M.D., Donna Floyd-Gimons, R.N., and Melissa House, R.N.; Baylor University Medical Center (Dallas, TX): Ronald Hogg, M.D., and Tammy Fisher, R.N.; California Pacific Medical Center (San Francisco, CA): Susan Conley, M.D., and Deborah Acres, R.N.; Cedars-Sinai Medical Center (Los Angeles, CA): Elaine Kamil, M.D., and Cathy Vogt, R.N.; Children’s Hospital and Medical Center (Seattle, WA): Sandra L. Watkins, M.D., Louise Peck, R.N., and Kelly McCarthy, R.N.; Children’s Hospital Medical Center (Cincinnati, OH): Fred Strife, M.D.; Children’s Hospital of Buffalo (Buffalo, NY): Leonard Feld, M.D., and Cathy Sherin, R.N.; Children’s Memorial Hospital (Chicago, IL): Craig Langman, M.D., and Katy Schmeissing, R.N, M.S.; Children’s Mercy Hospital Medical Center (Kansas City, MO): Bradley Warady, M.D., and Gina Weddle, R.N.; Children’s National Medical Center (Washington DC): Mary Ellen Turner, M.D.; Cook Children’s Hospital (Fort Worth, TX): William Allen, M.D., Watson Arnold, M.D., and Peggy Brigance, R.N.; Crippled Children’s Foundation Research Center (Memphis, TN): Robert Wyatt, M.D., and Paula Miller, R.N.; Loma Linda University Medical Center (Loma Linda, CA): Shoba Sahney, M.D., and Sandi Swiridoff, R.N.; University of Oklahoma (Oklahoma City, OK): Adolfo Garnica, M.D., and James Wenzl, M.D.; Tulane University Medical Center (New Orleans, LA): Frank Boineau, M.D., Karen Welling, R.N., M.S.N., and Melissa Parenti, R.N.; University of Alabama (Birmingham, AL): Edward Kohaut, M.D., and Sandra Overstreet, R.N.; University of California (Los Angeles, CA): Robert Ettenger, M.D., Ora Yadin, M.D., and Lila Moulton, R.N.; University of Chicago Children’s Hospital (Chicago, IL): Sharon Bartosh, M.D., and Eileen Swanson, R.N.; University of Colorado Health Sciences Center (Denver, CO): Douglas Ford, M.D., Carol Salbenblatt, R.N., and Terri Bisio, R.N.; University of Texas Medical Branch (Galveston, TX): Alok Kalia, M.D., Ann Burns, R.N., and Mary Ann Armendaiz, R.N.; University of Texas Medical School (Houston, TX): Ronald Portman, M.D., and Patty Brannan, R.N.; University of Texas Southwestern Medical Center (Dallas, TX): Steven Alexander, M.D., and Nancy Simonds, R.N.; University of Utah Medical Center (Salt Lake City, UT): Miriam Turner, M.D., Richard Siegler, M.D., and Carolyn Wagner-Munford, R.N.; and University of Virginia (Charlottesville, VA): Robert Chevalier, M.D., Fern Campbell, R.N. Southwest Pediatric Nephrology Study Group Central Office: Columbia Hospital at Medical City (Dallas, TX): Ronald J. Hogg, M.D., Director; Kaye Green, Administrative Coordinator.

Received April 29, 1998.

Revised October 27, 1998.

Accepted November 9, 1998.

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