Serum insulin-like growth factors (IGFs) and IGF binding proteins 1, 2, and 3 in children with chronic renal failure: relationship to height and glomerular filtration rate. The European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood.

Abstract

Serum levels of insulin-like growth factor I (IGF-I), IGF-II, and IGF binding protein 1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured in 94 children with chronic renal failure (CRF). The results were compared with their respective age-dependent normal ranges, and the relationship with height and residual glomerular filtration rate (GFR) was examined. Each IGF and IGFBP was quantified by specific RIA. Serum IGF-I and IGF-II levels were in the normal range throughout their entire childhood in the vast majority of cases. The mean age-related IGF-I (0.07 +/- 0.14 SD score) and IGF-II levels (0.06 +/- 0.11 SD) were similar. Age-related IGF-II but not IGF-I levels showed a weak inverse linear correlation with residual GFRs (r = -0.24, P < 0.02). Mean age-related IGFBP-1 serum levels (1.04 +/- 0.09 SD) were slightly elevated, whereas mean age-related serum IGFBP-2 levels (3.25 +/- 0.20 SD) and serum IGFBP-3 levels (2.61 +/- 0.12 SD) were markedly elevated. Significant inverse correlations were found between GFRs and age-related IGFBP-1 (r = -0.42, P < 0.001), IG-FBP-2 (r = -0.56, P < 0.001), and IGFBP-3 (r = -0.28, P < 0.005), but the increase in IGFBP-2 with declining GFR was relatively more pronounced than the respective increase in IGFBP-1 and IGFBP-3. The correlation between age-related IGF-I and relative height in prepubertal children with CRF (n = 54, r = 0.43, P < 0.001) was lower than in prepubertal controls (n = 68, r = 0.67, P < 0.001), and the slope of the regression line was significantly less steep, indicating that the normal relationship between IGF-I and height is disturbed in CRF. The normal relationship between IGFBP-3 and height was disrupted in CRF. Forward stepwise regression analysis revealed that height in CRF is correlated with IGF-I and inversely correlated with IGFBP-2. We conclude that the imbalance between normal IGFs and excessive IGFBP serum levels in CRF plays a pathogenic role in the growth failure of these children.

Are insulin-like growth factor and its binding proteins 1 and 3 clinically useful as markers of malnutrition, sarcopenia and inflammation in end-stage renal disease?

“…In diabetics patients without renal disease, insulin is thought to be an important determinant of IGFBP-1 production and thus of IGF-I bioavailability (Kaufman and Catanese, 1995), and our observation of a strong correlation between insulin, glucose and IGFBP-1 agree with those reported previously in children with ESRD (Tonshoff et al, 1995) and in HD patients . Indeed, IGFBP-1 production in the liver is known to be strongly influenced by carbohydrate intake (Wolk et al, 2004), and administration of recombinant IGFBP-1 leads to increased secretion of insulin in rats (Mortensen et al, 1997), whereas IGF-I is known to counteract GH-induced suppression of insulin synthesis (Moses et al, 1996).…”

“…However, whereas IGF-I and IGFBP-3 were found to be within the normal range, levels of IGFBP-1 were increased almost threefold in type II diabetic and non-diabetic patients, and almost sevenfold in type I diabetic patients, as compared to the normal levels reported by the kit manufacturer. This is in agreement with previous studies in ESRD (Tonshoff et al, 1995;Frystyk et al, 1999;Iglesias et al, 2004). Thus, while IGF-I does not appear to correlate well with GFR (Iglesias et al, 2004), ESRD may instead result in disturbances of both synthesis and bioavailability of IGF-I through effects on its binding proteins, as well as through the generally elevated levels of GH (Tonshoff et al, 1995;Divino Filho et al, 1998) seen in these patients.…”

“…Taken together, although some findings suggest a role for IGF-I in the causal pathway leading to sarcopenia in the elderly (Cappola et al, 2001), further studies are clearly needed to clarify the pathways involved and their relative importance in ESRD. The amount of free IGF-I able to act upon the target receptors is also very much dependent on at least six different IGF-binding proteins, the two most prominent in the systemic circulation being IGFBP-1 and IGFBP-3 (Tonshoff et al, 1995;Frystyk et al, 1999), levels of which are altered in renal failure (Ding et al, 1997;Iglesias et al, 2004). Whereas the main source of circulating IGF-I and IGFBP-1 is considered to be the liver (Brismar et al, 1994), the main source(s) of circulating IGFBP-3 is not known.…”

The growth hormone–insulin-like growth factor-I axis in chronic kidney disease

“…Serum IGFBP-1, -2, -4, and -6 levels are elevated, as are immunoreactive IGFBP-3 levels, although the latter is largely the result of the accumulation of immunoreactive fragments with reduced IGF-I affinity; intact IGFBP-3 levels are not elevated [52][53][54][55]. The bioavailability of IGF-I in CKD is compromised because of increased levels of IGFBP-1, -2, -4, and -6 [48][49][50].…”

“…Moreover, administration of GH to rats with puromycin-aminoglycoside-induced CKD accelerates the development of glomerulosclerosis [76]. Furthermore, GH administration accelerates glomerulosclerosis and CKD progression in partially nephrectomized rats [52]. Mice transgenic for GH develop mesangial proliferation and progressive glomerular sclerosis [77].…”