Abstract
Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) were studied in children with end-stage renal failure (ESRF,n=31) and chronic renal failure (n=11) with residual glomerular filtration. Somatomedin bioactivity in patient sera was found to be decreased while IGF-I and IGF-II levels by radio-immunoassay (RIA) were normal. In contrast, IGFBP-1 and IGFBP-3 levels (measured by RIA) were markedly increased in uraemia. Excess IGFBP was shown to be able to bind IGF by determination of the free IGF binding capacity. Using high-performance liquid chromatography a shift of the IGFBP-3 profile to low molecular weight components could be demonstrated in ESRF. Affinity crosslinking experiments showed that these low molecular weight IGFBP-3 immunoreactive forms are biologically active. In normal urine only IGFBP-3 forms smaller than 60 kDa were detected with a major peak at 12–20 kDa. Removal of excessive IGFBP from patient sera by affinity chromatography on an IGF-II Sepharose column resulted in a significant increase in somatomedin bioactivity. Model calculations on the interaction of IGF and IGFBP using empirical data suggested a reduction of IGF secretion in uraemia by an order of magnitude. It is concluded: (1) that renal failure causes an accumulation of low molecular weight IGFBP, (2) that the resulting excess of IGFBP acts as a somatomedin inhibitor, and (3) that in uraemia there is a relative growth hormone resistance with respect to IGF production.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Mehls O, Ritz E, Hunziker EB, Tönshoff B, Heinrich U (1988) Role of growth hormone in growth failure of uraemia: perspectives for application of recombinant growth hormone. Acta Paediatr Scand [Suppl] 343: 118–126
Powell DR, Rosenfeld RG, Baker BK, Liu F, Hintz RL (1986) Serum somatomedin levels in adults with chronic renal failure: the importance of measuring insulin-like growth factor I (IGF-I) and IGF-II in acid-chromatographed uraemic serum. J Clin Endocrinol Metab 63:1186–1192
Powell DR, Rosenfeld RG, Sperry JB, Baker BK, Hintz RL (1987) Serum concentrations of insulin-like growth factor (IGF)-I, IGF-2 and unsaturated somatomedin carrier proteins in children with chronic renal failure. Am J Kidney Dis 10: 287–292
Schwalbe SL, Betts PR, Rayner PH, Rudd BT (1977) Somatomedin in growth disorders and chronic renal insufficiency in children. Br Med J 1: 679–682
Phillips LS, Pennisi AJ, Belosky DC, Uittenbogaart C, Ettenger RB, Malekzadeh MH, Fine RN (1978) Somatomedin activity and inorganic sulfate in children undergoing hemodialysis. J Clin Endocrinol Metab 46: 165–168
Phillips LS, Fusco AC, Unterman TG, Del Creco F (1984) Somatomedin inhibitor in uraemia. J Clin Endocrinol Metab 59: 764–772
Ballard J, Baxter R, Binoux M, Clemmons D, Drop S, Hall K, Hintz R, Rechler M, Rutanen E, Schwander J (1989) On the nomenclature of the IGF binding proteins. Acta Endocrinol (Copenh) 121: 751–752
Brinkman A, Groffen C, Kortleve DJ, Geurts van Kessel A, Drop SLS (1988) Isolation and characterization of a cDNA encoding the low molecular weight insulin-like growth factor binding protein (IBP-1). EMBO J 7: 2417–2423
Julkunen M, Koistinen R, Aalto-Setälä K, Seppälä M, Jänne OA, Kontula K (1988) Primary structure of human insulin-like growth factor-binding protein/placental protein 12 and tissue specific expression of its mRNA. FEBS Lett 236: 295–302
Lee Y-L, Hintz RL, James PM, Lee PDK, Shively JE, Powell DR (1988) Insulin-like growth factor (IGF) binding protein complementary deoxyribonucleic acid from human HEP G2 hepatoma cells: predicted protein sequence suggests an IGF binding domain different from that of the IGF-I and IGF-II receptors. Mol Endocrinol 2: 404–411
Wood WI, Cachianes G, Henzel WJ, Winslow GA, Spencer SA, Hellmiss R, Martin JL, Baxter RC (1988) Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein. Mol Endocrinol 2: 1176–1185
Binkert C, Landwehr J, Mary JL, Schwander J, Heinrich G (1989) Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2). EMBO J 8: 2497–2502
Baxter RC, Martin JL (1986) Radioimmunoassay of growth hormone-dependent insulin-like growth factor binding protein in human plasma. J Clin Invest 78: 1504–1512
Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR (1990) A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70: 1292–1298
Baxter RC (1988) Characterization of the acid-labile subunit of the growth hormone-dependent insulin-like growth factor binding protein complex. J clin Endocrinol Metab 67: 265–272
Blum WF, Ranke MB (1990) Insulin-like growth factor-binding proteins (IGFBPs) with special reference to IGFBP-3. Acta Paediatr Scand [Suppl] 367: 55–62
Van den Brande JL, Du Caju MVL (1974) An improved technique for measuring somatomedin activity in vitro. Acta Endocrinol (Copenh) 75: 233–242
Blum WF, Ranke MB, Bierich JR (1986) Isolation and partial characterization of six somatomedin-like peptides from human plasma Cohn fraction IV. Acta Endocrinol (Copenh) 111: 271–284
Blum WF, Ranke MB, Bierich JR (1988) A specific radioimmunoassay for insulin-like growth factor II: the interference of IGF binding proteins can be blocked by excess IGF-I. Acta Endocrinol (Copenh) 118: 374–380
Wilkins JR, D'Ercole AJ (1985) Affinity-labeled plasma somatomedin-C/insulin-like growth factor I binding proteins. Evidence of growth hormone dependence and subunit structure. J Clin Invest 75: 1350–1358
Ranke MB, Blum WF, Bierich JR (1988) Clinical relevance of serum measurements of insulin-like growth factors and somatomedin binding proteins. Acta Paediatr Scand [Suppl] 347: 114–126
Blum WF, Ranke MB, Kietzmann K, Tönshoff B, Mehls O (1989) Excess of IGF-binding proteins in chronic renal failure: evidence for relative GH resistance and inhibition of somatomedin activity. In: Drop SLS, Hintz RL (eds) Insulin-like growth factor binding proteins. Excerpta Medica, Amsterdam, pp 93–101
Lee PDK, Hintz RL, Sperry JB, Baxter RC, Powell DR (1989) IGF binding proteins in growth-retarded children with chronic renal failure. Pediatr Res 26: 308–315
Hall K, Lundin G, Povoa G (1988) Serum levels of the low molecular weight form of insulin-like growth factor binding protein in healthy subjects and patients with growth hormone deficiency, acromegaly and anorexia nervosa. Acta Endocrinol (Copenh) 118: 321–326
Baxter RC, Cowell CT (1987) Diurnal rhythm of growth hormoneindependent binding protein for insulin-like growth factors in human plasma. J Clin Endocrinol Metab 65: 432–440
Suikkari AM, Rutanen EM, Seppala M (1987) Circulating levels of immunoreactive insulin-like growth factor-binding protein in nonpregnant women. Hum Reprod 2: 297–300
Liu F, Powell DR, Hintz RL (1990) Characterization of insulin-like growth factor-binding proteins in human serum from patients with chronic renal failure. J Clin Endocrinol Metab 70: 620–628
Guler HP, Zapf J, Schmid C, Froesch ER (1989) Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol (Copenh) 121: 753–758
Goldberg AC, Trivedi B, Delmez JA, Harter HR, Daughaday WH (1982) Uremia reduces serum insulin-like growth factor I, increases insulin-like growth factor II, and modifies their serum protein binding. J Clin Endocrinol Metab 55: 1040–1045
Blum WF, Ranke MB, Jenne EW, Kietzmann K, Bierich JR (1989) The physiological role of IGF binding protein. In: Frisch H, Thorner MO (eds) Hormonal regulation of growth. Raven, New York, pp 153–170
Koch VH, Lippe BM, Nelson PA, Boechat MI, Sherman BM, Fine RN (1989) Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure. J Pediatr 115: 365–371
Tönshoff B, Mehls I, Heinrich U, Blum WF, Ranke MB, Schauer A (1990) Growth-stimulating effects of recombinant human growth hormone in children with end-stage renal disease. J Pediatr 116: 561–566
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Blum, W.F., Ranke, M.B., Kietzmann, K. et al. Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia. Pediatr Nephrol 5, 539–544 (1991). https://doi.org/10.1007/BF01453697
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01453697