Insulin-like growth factor binding proteins as growth inhibitors in children with chronic renal failure

Children with chronic renal failure (CRF) often fail to attain an adult height consistent with their genetic potential. The growth hormone (GH)/insulin-like growth factor (IGF)/growth plate chondrocyte axis has been intensively studied in these children to determine the basis for this growth failure. Evidence suggests that hepatic GH resistance results in deficient expression of IGF-I. However, serum IGF-I levels are usually normal and it is IGF-I action on target tissues which is inhibited, possibly by the presence of excess high-affinity IGF binding proteins (IGFBPs) in CRF serum. In this paper we evaluate the roles of IGFBP-1, -2, and -3 as growth inhibitors in CRF children. The data support a role for each of these IGFBPs as growth inhibitors. Currently, IGFBP-1 meets most criteria expected of a growth inhibitor, but IGFBP-2 and -3 will likely also meet these criteria and may well be important contributors to the growth failure of CRF. Ultimately, many or all of the six IGFBPs may be found to contribute to the excess high-affinity IGF binding sites which are a hallmark of CRF serum and are possible contributors to the growth failure of CRF children.     

Serum insulin-like growth factors and their binding proteins in children with end-stage renal disease

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 54 children with end-stage renal disease (ESRD). The results were compared with their respective age-dependent normal ranges. IGFs and IGFBPs were quantified by specific radioimmunoassay. Serum IGF-I in children with ESRD tended to cluster in the low-normal range. Mean age-related serum IGF-I levels were slightly, but significantly decreased (–1.08±0.17 SDS). In view of the prevailing elevated growth hormone levels in ESRD, these serum, IGF-I levels must be interpreted as inadequately low. In contrast to IGF-I, individual serum IGF-II levels were either in the uppernormal range or clearly elevated. Mean age-related IGF-II (1.09±0.15 SDS) was lightly, but significantly elevated. Mean age-related IGFBP-1 serum levels (2.20±0.10 SDS) were moderately increased, while mean age-related serum IGFBP-2 (5.65±0.36) and IGFBP-3 levels (3.60±0.19) were markedly elevated. Affinity cross-linking of¹²⁵iodine-IGF-II to sera from patients with ESRD and immunoprecipitation with a specific antiserum showed that low molecular weight IGFBP-3 fragments in ESRD serum are capable of binding IGF. In patients with ESRD, a rapid and persistent decline of immunoreactive IGFBP-3 in response to restoration of renal function by renal transplantation was observed. This finding indicates that renal dysfunction contributes to high immunoreactive, IGFBP-3 levels in ESRD. In conclusion, the imbalance between normal total IGF levels and the excess of IGFBPs in ESRD is likely to play a role in growth failure in these children.     

Characterization of insulin-like growth factors and their binding proteins in peritoneal dialysate

.Serum insulin-like growth factors (IGFs), which circulate bound to specific IGF binding proteins (IGFBPs), must exit the intravascular space before acting on target tissues. Little is known about the nature of IGF/IGFBPs in extravascular fluids of patients with chronic renal failure (CRF). Peritoneal dialysate (PD) was studied since, after a short incubation, PD contains proteins which have entered an extravascular space; thus, IGF/IGFBP forms in PD are more likely than serum forms to interact with target tissues. IGF-I and IGF-II, and IGFBPs 1 – 4, were readily identified by specific immunoassays and/or ¹²⁵iodine-IGF ligand blotting of simultaneously obtained PD and serum samples from seven CRF children; IGFBP-3 was a major IGFBP in PD as in serum. Where quantitated, IGF and IGFBP levels in PD were approximately 10% of serum concentrations. After separation of PD and serum by size-exclusion chromatography, serum had more IGFBP-3 in 150-kilodalton (kDa) than 35-kDa fractions, while PD had far less IGFBP-3 in 150-kDa than 35-kDa fractions. Immunoblot studies revealed a major 29-kDa IGFBP-3 fragment, in addition to intact 41- and 38-kDa IGFBP-3 forms, in PD and CRF serum; the 29-kDa form predominated in the 35-kDa PD fractions. These data suggest that the 29-kDa fragment is the IGFBP-3 form most likely to modulate IGF effects on target tissues of CRF individuals. Received: April 17, 1995; received in revised form September 19, 1995; accepted October 12, 1995     

Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate

Growth retardation in children with chronic renal failure (CRF) is partly due to an inhibition of insulin-like growth factor (IGF) activity by an excess of high-affinity IGF-binding proteins (IGFBPs). The aim of this study was to analyze the serum levels and forms of IGFBP-4 and IGFBP-5 in CRF patients using specific, recently developed radioimmunoassays (RIAs) and immunoblot analysis. We examined 89 children [age 11.5 (2.8–19.0) years] with CRF [glomerular filtration rate 26.6 (7.0–67.4) ml/min per 1.73 m²], nine of them with end-stage renal disease undergoing peritoneal dialysis. Serum-immunoreactive IGFBP-4 levels were fourfold increased in CRF (prepubertal 1080±268 ng/ml; pubertal 989±299 ng/ml) compared to healthy prepubertal controls (265±73 ng/ml). In contrast, serum IGFBP-5 levels were not significantly increased neither in prepubertal (361±120 ng/ml vs 282±75 ng/ml in controls) nor pubertal CRF children (478±165 ng/ml vs 491±80 ng/ml in controls). Immunoblot analysis showed the presence of intact as well as fragmented IGFBP-4 and IGFBP-5. Serum IGFBP-4, but not IGFBP-5, levels were inversely correlated with GFR (r=–0.39, P<0.001). In prepuber- tal children, IGFBP-4 levels were inversely correlated with standardized height (r=–0.40; P<0.005). In contrast, IGFBP-5 levels were positively correlated both with standardized height (r=0.32, P<0.02) and baseline height velocity (r=0.45, P<0.005). A 3-month therapy with rhGH stimulated serum IGFBP-5 levels by 43% (P<0.01); there was no consistent effect on IGFBP-4 levels. There was a positive correlation between IGFBP-4 and IGFBP-2 (r=0.46, P<0.001); IGFBP-5 was positively correlated with IGF-I (r=0.59, P<0.001), IGF-II (r=0.42, P<0.001) and IGFBP-3 (r=0.47, P<0.001) and inversely correlated with IGFBP-1 (r=–0.41, P<0.001). In summary, serum IGFBP-4 is fourfold elevated in children with CRF in relation to the degree of renal dysfunction and contributes to the marked increase in IGF-binding capacity in CRF serum. The inverse correlation of serum IGFBP-4 with standardized height is consistent with its role as another inhibitor of the biological action of the IGFs on growth plate cartilage. In contrast, serum IGFBP-5 is not elevated in CRF serum and circulates mainly as proteolysed fragments. The positive correlation of serum IGFBP-5 with growth and its increase during GH therapy indicate that IGFBP-5 is a stimulatory IGFBP in patients with CRF, either by enhancing IGF activity through better presentation of IGF to its receptor or by an IGF-independent effect through activation of a specific, recently described putative IGFBP-5-receptor. Received: 24 September 1999 / Revised: 6 January 2000 / Accepted: 13 January 2000 / Accepted: 13 January 2000     

Peritoneal loss of insulin-like growth factor-I and binding proteins in end-stage renal disease

The kinetics of peritoneal transport of insulin-like growth factor (IGF) system-related proteins during dialysis is not well characterized. We studied temporal changes in dialysate and serum concentrations of IGF-I and IGF-II as well as IGF binding protein (BP)-1, -2, and -3 in ten children with end-stage renal disease (ESRD) undergoing continuous cycling peritoneal dialysis (CCPD) during a 4-h peritoneal equilibration test (PET). Dialysate concentrations of IGF-I, IGF-II, and all three IGFBPs demonstrated a time-dependent increase during PET. Despite their transport, the serum concentrations of these proteins did not change significantly during the PET. Dialysate/serum ratios for IGF-I, IGF-II, and IGFBP-1, -2, and -3 were significantly increased at 2 h and increased further at 4 h, at which time values averaged 1.3±0.2%, 3.1±0.5%, 6.2±1.0%, 2.4±0.2%, and 1.3±0.2% of serum levels, respectively. The transperitoneal clearance (μl/min per 1.73 m²) of the three IGFBPs was inversely related to both their molecular weight and plasma concentration. However, peritoneal clearance of IGF-I and -II was similar to that of the larger and more-abundant IGFBP-3. Mass transfer rates (μg/h per 1.73 m²) for the IGFs and their binding proteins were directly proportional to their prevailing plasma concentration. Based on estimates of mass transfer, only a small molar excess of IGFBPs was removed from the circulation relative to the combined molar concentration of IGF-I and IGF-II. Hence, it seems unlikely that any beneficial effect of CCPD on growth in children with ESRD is mediated via a preferential loss of IGFBPs into the dialysate fluid. Received August 15, 1997; received in revised form January 7, 1998; accepted January 9, 1998     

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 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.     

Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure

Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure. BACKGROUND: Chronic renal failure (CRF) results in major changes in the circulating growth hormone (GH)/insulin-like growth factor (IGF) system. However, there are only limited data on changes in free IGF-I in CRF. METHODS: Matched groups of nondiabetic, nondialyzed patients with CRF (N = 25) and healthy controls (N = 13) were compared. The creatinine clearance (CCr) based on a 24-hour urine collection ranged from 3 to 59 and 89 to 148 ml/min/1.73 m2 in patients and controls, respectively. Overnight fasting serum samples were analyzed for free and total IGF-I and -II, and IGF-binding protein (IGFBP)-1, -2, and -3. Additionally, intact as well as proteolyzed IGFBP-3 was determined. RESULTS: The patients had reduced serum-free IGF-I (-53%) and increased levels of total IGF-II (40%), IGFBP-1 (546%), and IGFBP-2 (270%, P < 0.05). Serum total IGF-I and free IGF-II were normal. Also, serum levels of immunoreactive IGFBP-3 were elevated (33%, P < 0.05), but this could be explained by an increased abundance of IGFBP-3 fragments, as ligand blotting showed no difference in levels of intact IGFBP-3. Accordingly, patients had an increased proteolysis of IGFBP-3 in vivo (17%) and in vitro (7%, P < 0.05). In patients, free IGF-I levels correlated positively with CCr (r2 = 0.38, P < 0.002) and inversely with IGFBP-1 (r2 = 0.69, P < 0. 0001) and IGFBP-2 (r2 = 0.41, P < 0.0007), whereas CCr was inversely correlated with levels of IGFBP-1 (r2 = 0.48, P < 0.0001) and IGFBP-2 (r2 = 0.63, P < 0.0001). CONCLUSIONS: These data strongly support the hypothesis that CRF-related growth failure and tissue catabolism are caused by an increased concentration of circulating IGFBP-1 and -2, resulting in low serum levels of free IGF-I and thus IGF-I bioactivity. In addition, low levels of free IGF-I may explain the increased secretion of GH in CRF.     

Insulin-like growth factor binding protein (IGFBP) displacers: relevance to the treatment of renal disease

Chronic renal failure (CRF) results in complex metabolic and hormonal derangements, particularly in the GH-IGF-IGFBP axis, which can be manifest in children as growth retardation. The decreased glomerular filtration rate (GFR) in CRF is associated with increased plasma IGFBP levels, which may have an important role in inhibiting the bioavailability of IGF-I. There is a large literature from both animal and human studies showing that the administration of IGF-I can affect structure and function of normal and compromised kidneys. We propose an alternative therapeutic approach: activating bound IGF by administering molecules that bind to the IGFBPs. In initial animal studies we used a mutant IGF, an IGF displacer, that binds to IGFBPs but not to IGF receptors. In the rat this molecule activated the IGF system and produced IGF-like effects in vivo, such as increased kidney size, reduced serum creatinine, increased bone growth and increased body weight. Novel synthetic peptides have also been discovered which bind to specific IGFBPs, and we believe such molecules hold promise as therapeutic agents in renal disease. Received: 12 April 1999 / Revised: 21 December 1999 / Accepted: 27 December 1999     

Evaluation of IGF system component levels and mitogenic activity of uremic serum on normal human osteoblasts

To test the hypothesis that impairment in bone formation in renal osteodystrophy in adults with chronic renal failure (CRF) might be mediated in part by alterations in circulating levels of the insulin-like growth factor (IGF) system components, we compared serum levels of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, IGFBP-4 and IGFBP-5 in adults with CRF (CRF patients with parathyroid hormone (PTH) < 100 pg/ml, PTH > 300 pg/ml and end-stage renal failure (ESRF) patients) versus age-matched controls. To evaluate the biological significance of alterations in circulating level of IGF system components, we compared the mitogenic activity of the sera on proliferation of normal human osteoblasts in vitro by using [(3)H]thymidine incorporation. We found severalfold increased serum levels of IGFBP-3 (2-fold), IGFBP-4 (5-fold) and slightly increased IGF-II levels in ESRF patients as well as a 2.6-fold increase in free IGF-I in CRF patients with PTH < 100 pg/ml. The mitogenic activity was found to be increased in serum of kidney failure patients compared to controls. This was most pronounced in CRF patients with PTH < 100 pg/ml showing also a significant increase in free IGF-I and the lowest levels of the IGF-inhibitory IGFBP-4. Our data support the hypothesis that alterations in serum levels of stimulating (i.e. free IGF-I) and inhibitory IGF system components (i.e. IGFBP-4) may influence osteoblastic cell proliferation in renal osteodystrophy.     

Effect of chronic renal failure and prednisolone on the growth hormone-insulin-like growth factor axis

Abnormalities of the growth hormone (GH)/ insulin-like growth factor (IGF) axis have been reported in children with chronic renal failure (CRF) and post-transplant, and are thought to contribute to poor growth. This study examined the effect of CRF and steroid therapy (given post-transplant and to children with normal renal function) on the GH-IGF axis in children with normal and abnormal growth. Thirty-one children with CRF, ten on dialysis, 26 with renal transplants and ten taking steroid therapy but with normal renal function, were studied. IGF-I, measured by radioimmunoassay, was normal but IGF bioactivity was low in groups with a decreased glomerular filtration rate (P<0.05). Transplanted children growing at a subnormal growth rate had lower IGF bioactivity than those growing at a normal rate (P=0.03), but there was no such difference in bioactivity in children with CRF. There was no correlation between IGF bioactivity and prednisolone treatment. There was no correlation between IGF binding proteins 1, 2 or 3 and growth. Received: 1 August 2000 / Revised: 11 July 2001 / Accepted: 12 July 2001     

The multi-functional role of insulin-like growth factor binding proteins in bone

The insulin-like growth factor (IGF) system is an important regulator of bone formation. The IGFs (IGF-I and IGF-II) are the most abundant growth factors produced by bone, and are regulated by their six high affinity binding proteins (IGFBPs). The IGFBPs are produced by osteoblasts and are responsible for transporting the IGFs and extending their half-lives. In general, IGFBP-1, -2, -4, and -6 inhibit and IGFBP-3 and –5 stimulate osteoblast function. IGFBP-4 and -5 are the most abundant IGFBPs produced by osteoblasts, and therefore they are the primary focus of this review. IGFBP-5 is an important stimulator of bone formation and may also function independently of IGFs. IGFBP-4 inhibits osteoblast function by sequestering IGF and preventing it from binding to its receptor. This review focuses on the specific IGF-dependent and IGF-independent roles of the IGFBPs in bone formation, as well as their potential mechanisms of action. In addition, discussion of the regulation of the IGFBPs by post-translational modification (i.e., proteolysis) has been included. Studies on the regulation of production and actions of IGFBPs suggest that the IGFBP system in bone is pleiotropic and capable of serving multiple effector inputs from systemic and local sources.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Insulin-like growth factor binding protein-3 protease activity in the urine of children with chronic renal failure

The insulin-like growth factors, IGF-1 and IGF-II, are polypeptides that potentiate cellular growth. In addition to binding to specific cell surface receptors, the IGFs bind with high affinity to a family of proteins, the insulin-like growth factor binding proteins (IGFBPs). Serum and urine IGFBP patterns are altered in individuals with chronic renal failure (CRF). We recently reported that the urinary IGFBP pattern of CRF patients is unique for increased insulin-like growth factor binding protein-1 (U-IGFBP-1) levels. In this study, we used western ligand blotting (WLB), western immunoblotting (WIB), and radioimmunoassay (RIA) to further evaluate serum and urine IGFBP profiles of children with CRF (n=14). Five patients with CRF displayed decreased serum IGFBP-3 profiles by WLB. Serum IGFBP-3 WIB profiles were remarkable for 30- and 20-kDa fragments of IGFBP-3 not seen in control serum. Serum IGFBP-3 levels, as determined by RIA, were slightly elevated. Serum levels of IGFBP-2 also were increased, although not at a level reaching statistical significance. WLB of CRF urine revealed a large increase in U-IGFBP-1 and a complete absence of urinary IGFBP-3. Recent studies of serum from pregnant women and seminal plasma have demonstrated a similar absence of intact IGFBP-3, due to the presence of a specific IGFBP-3 protease. To evaluate whether an IGFBP-3 protease accounts for the absence of intact U-IGFBP-3 in children with CRF, urine and serum samples from individuals with CRF and controls were tested. An IGFBP-3 protease assay using concentrated urine revealed the presence of two distinct proteases found only in the CRF urines. Serum IGFBP-3 protease activity was no greater in patients with CRF than in controls. We conclude that the decrease in intact urinary IGFBP-3 is due to proteolysis by an IGFBP-3 protease.     

Insulin-Like Growth Factor–I Treatment to Enhance Renal Function in Advanced Chronic Renal Failure

Because of the potential for IGF-1 to enhance renal function in advanced chronic renal failure (CRF) we set out to determine whether IGF-1 can induce a sustained increase in renal function in patients with near end-stage renal failure. To this end we first examined the impact of CRF on the pharmacokinetics of IGF-1 and then we examined the effect of prolonged IGF-I treatment on the renal function of patients with an average GFR of 17mL/min/1.73m². Interestingly the metabolic clearance rate of IGF-1 in CRF subjects was similar to that in normal subjects even though the total serum IGF-1 levels rose to higher maximum levels. This increase was due to a reduced volume of IGF-1 distribution, a consequence of the elevated serum IGF binding proteins in CRF subjects. Treatment with IGF-I (60 mg/kg twice daily sc) for 31 days resulted in a 14% and 18% increase in the inulin and PAIL clearances respectively (n = 6 patients). These parameters returned to basal levels on stopping treatment. Serum immunoreactive IGFBP-3 levels fell and IGFBP-2 and -3 levels rose during IGF-1 therapy. Adverse effects were mild, of short duration and easily manage-able. Thus IGF-I pharmacokinetics are largely unchanged in CRF and the administration of IGF-1 produces a modest improvement in the GFR. These results appear to justify more extensive examination of the therapeutic role of IGF-1 in the treatment of CRF.     

Influence of growth hormone and insulin-like growth factor-I on kidney function and kidney growth

Decreased glomerular filtration rate (GFR) in hypopituitarism and increased GFR in acromegaly suggest that growth hormone (GH) has a substantial effect on renal haemodynamics. Extractive and recombinant human (rh) GH in healthy volunteers increased effective renal plasma flow (ERPF) and GFR by 10% and 15% respectively. Renal response to GH was delayed and occurred at the same time as an increase in plasma insulin-like growth factor (IGF)-I values, whereas infusion of rhIGF-I promptly increased GFR and ERPF, indicating that the haemodynamic response of the kidney to GH is mediated by IGF-I. In chronic renal failure (CRF), the acute effect of GH on GFR is obliterated. This might protect the diseased kidney against the undesired consequences of hyperfiltration. Indeed, rhGH treatment for 1 year in children with CRF did not lead to an accelerated decline in GFR compared with the year before treatment. GH and IGF-I also effect renal growth. Exposure to excessive GH in transgenic mice causes renomegaly and progressive glomerular selerosis. In acromegalic humans, increased renal size and weight and increased glomerular diameter are well known, whereas renal failure is not a long-term hazard. At least in normal and hypophysectomized rats treated with doses comparable with the therapeutic regimens used in stunted children, rhGH increased renal weight but in proportion to the increase in body weight indicating an isometric effect of GH on renal growth. From these data, major renal longterm side effects of rhGH treatment in children with CRF appear unlikely.     

Effects of growth hormone on insulin-like growth factors and binding proteins before and after renal transplantation

A bstract. Three short children with severe chronic renal failure were treated with recombinant human growth hormone (rhGH) for 2 years. Each received a transplant in the 2nd year. Serum collected before and during rhGH therapy was analysed retrospectively by Western ligand blot and immunoblotting techniques. In addition, radioimmunoassays for insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), acid-labile subunit (ALS) and IGFBP-1 were performed. IGFBPs in serum, detected by Western ligand blot, were identified as IGFBP-3, -2, -1 and -4 by immunoblot. The serum concentration of IGF-I in each child rose approximately fourfold with rhGH before transplantation and subsequently remained elevated. IGFBP-3 levels rose to double the pretreatment value, but dropped to normal levels following transplantation, while ALS rose with rhGH treatment and remained increased after transplantation. IGFBP-1 levels changed little with rhGH but fell following transplantation. A low molecular weight form of IGFBP-3 was noted at 30 kilodaltons on immunoblot which was not clearly seen on the ligand blot. IGFBP-2 was present as a distinct band on Western ligand blot before transplantation and appeared decreased in intensity subsequently. IGFBP-1, seen on immunoblot clearly before transplant, disappeared after the transplant. rhGH successfully improved growth in these children, in association with a fourfold increase in IGF-I levels, which was maintained following transplantation. The reduction in IGFBPs following transplantation suggests correction of impaired clearance by the diseased kidney. Received September 5, 1994; received in revised form November 8, 1995; accepted November 21, 1995     

Distrubance of growth hormone-insulin-like growth factor axis in uraemia

The growth hormone/insulin-like growth factor (IGF) axis is disturbed in uraemia. Elevated plasma growth hormone (GH) levels despite diminished growth suggest GH resistance, which may be due in part to a decreased expression of the growth hormone receptor at the cell membrane. The hepatic production of IGFs under the control of GH is impaired. Furthermore, there is an excess of IGF-binding protein over total IGF as a consequence of reduced renal clearance of low-molecular-weight subunits of the IGF-binding protein (IGF-BP). This results in an absolute (diminished production) and a relative (low bioavailability) deficiency of IGF. Recombinant human growth hormone (rhGH) in doses of 4 IU/m² per day is able to induce catch-up growth in children with preterminal and terminal renal failure. The growth stimulation of exogenous GH is attributed to its potency to increase the ratio of IGF-I to IGF-BP, followed by a normalization of IGF bioactivity. In renal transplanted children growth is not only disturbed by decreased renal function but also by steroid treatment. Corticosteroids, are responsible for catabolism, for suppression of pituitary GH secretion and for inhibition of local production of IGFs. Exogenous rhGH is able to counteract these growth-inhibiting effects. However, it remains to be seen whether long-term GH treatment definitely improves final adult height.     

Insulin-like growth factors and risk of benign prostatic hyperplasia

BACKGROUND: Insulin-like growth factors (IGFs) have potent growth mitogenic and anti-apoptotic effects on prostate tissue, whereas IGF binding proteins (IGFBPs) inhibit growth of prostatic tissue. The IGF axis has been implicated in prostate cancer risk, but its role in benign prostatic hyperplasia (BPH) is unclear. METHODS: Plasma levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 were determined from the fasting bloods of 206 BPH cases admitted for treatment and 306 randomly selected population controls in Shanghai, China. RESULTS: Relative to the lowest tertile, men in the highest tertile of IGF-I levels had a significantly elevated risk of BPH (odds ratio [OR] = 2.80, 95% confidence interval [95% CI] = 1.60-4.92; P(trend) < 0.001). Results for IGF-I were more pronounced after adjustment for serum androgens. In contrast, men in the highest IGFBP-3 tertile had a significantly reduced risk (OR = 0.40; 95% CI = 0.23-0.69; P(trend) < 0.001). No associations of BPH with IGF-II and IGFBP-1 were observed. CONCLUSION: As has been previously observed for prostate cancer, we found that IGF-I and IGFBP-3 are associated with BPH risk in China. Further investigation is needed to elucidate the role of the IGF axis in BPH etiology.     

Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy

BACKGROUND: The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism. METHODS: In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values +/- SEM are given. RESULTS: With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover. CONCLUSION: Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.     

Increased insulin-like growth factor-II tissue concentrations during compensatory kidney growth in infantile rats

Insulin-like growth factor (IGF)-I and IGF-II serum and kidney tissue concentrations were measured in compensatory kidney growth in infantile and adult rats. We hypothesized that the known switch from IGF-II in fetal life to IGF-I in adult life may be responsible for the different modes of compensatory kidney growth, which are mainly characterized by hyperplasia in infantile rats and hypertrophy in adult rats. While IGF-I serum concentrations increased with age in infantile rats, kidney tissue concentrations of IGF-I showed a similar increase in both age groups after uninephrectomy. In adult rats, serum and kidney tissue concentrations of IGF-II were unchanged by uninephrectomy. In infantile rats, however, a significant increase in both serum and kidney concentrations of IGF-II was observed with a maximum at day 5 after uninephrectomy. To investigate if compensatory kidney growth is dependent on hyperperfusion of the remnant kidney, the left renal artery was clipped in infantile rats. The clipped kidney showed growth retardation despite normal kidney tissue concentrations of IGF-I and IGF-II. The contralateral kidney was enlarged and IGF-II kidney concentrations were elevated. However, animals with one clipped kidney and nephrectomy of the contralateral kidney showed compensatory kidney growth of the clipped kidney combined with increased IGF-II kidney tissue concentrations. We conclude that IGF-II mainly promotes compensatory kidney growth in infantile rats by hyperplasia. Hyperperfusion of the remnant kidney seems to be unnecessary for initiation of compensatory kidney growth.