Growth hormone resistance and inhibition of somatomedin activity by excess of insulin-like growth factor binding protein in uraemia.
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 cross-linking 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.
Blum
W F
WF
University Children's Hospital, Tübingen, Federal Republic of Germany.
Ranke
M B
MB
Kietzmann
K
K
Tönshoff
B
B
Mehls
O
O
D000293:Adolescent; D002352:Carrier Proteins / Q000097:blood / Q000302:isolation & purification / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid; D005919:Glomerular Filtration Rate; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007223:Infant; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism; D011863:Radioimmunoassay; D013002:Somatomedins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014511:Uremia / Q000378:metabolism*
D002352:Carrier Proteins; D018969:Insulin-Like Growth Factor Binding Proteins; D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D013006:Growth Hormone