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

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1 Pediatr Nephrol (1996) 10: PNA 1996 Pediatric Nephrology Review article Insulin-like growth factor binding proteins as growth inhibitors in children with chronic renal failure David R. PowelP, Frances Liu 2, Bonita K. Baker2, Phillip D. K. Lee 1, 3, and Raymond L. Hintz2 1 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA z Department of Pediatrics, Stanford University Medical Center, Stanford, California, USA 3 Diagnostic Systems Laboratories, Webster, Texas, USA Received July 7, 1995; received in revised form December 6, 1995; accepted December 15, 1995 Abstract. 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 highaffinity IGF binding sites which are a hallmark of CRF serum and are possible contributors to the growth failure of CRF children. Key words: Growth - Growth failure - Renal failure - Growth hormone - Insulin-like growth factor - Insulin-like growth factor binding proteins Introduction Children with chronic renal failure (CRF) achieve an adult height far below their genetic potential despite aggressive therapy with calories, alkali, phosphate binders, 1,25- dihydroxyvitamin D, dialysis, and transplantation [1]. Correspondence to: D. R. Powell, Texas Children's Hospital, Clinical Care Center, MC , 6621 Fannin Street, Houston, TX 77030, USA A search for uremic growth inhibitors has focused on the growth hormone (GH) - insulin-like growth factor (IGF) - growth plate chondrocyte (GPC) axis, which plays a central role in linear growth. GH and IGF act in synergy to stimulate proliferation and hypertrophy of GPCs; this is achieved partly because GH stimulates local IGF-I production by GPCs [1, 2]. In addition, GH raises serum IGF-I level by stimulating hepatic IGF-I production, and circulating IGF-I has now been clearly shown to stimulate linear growth in rats and humans [3-5]. However, despite profound growth failure in CRF children, initial studies found serum GH, IGF-I, and IGF-II levels to be normal or high in these children, suggesting that abnormalities of this axis were not responsible for the growth failure of CRF [1, 6-8]. A decade has passed since CRF serum was first noted to have an abnormally high IGF binding capacity; these IGF binding sites in CRF serum were of sufficiently high affinity to interfere with IGF assays by competing with IGF antisera and IGF receptors for IGF binding [7]. Since IGFs [7 kilodaltons (kda)] circulate in serum bound to IGF binding proteins (IGFBPs) in complexes of approximately 150 kda (major) and 35 kda (minor) [9], it was suspected that unsaturated forms of these serum IGFBPs accounted for the excess IGF binding capacity of CRF serum. Interest in the role of IGFBPs in the growth failure of CRF children led to the first reported molecular cloning of an IGFBP, IGFBP-1, in 1988 [10]. A total of six IGFBPs have now been cloned [11, 12] and are under intense study. IGFBP-1 and -2 are proteins of approximately 28 and 33 kda, respectively, which circulate in the 35-kDa serum fractions and are major contributors to the unsaturated IGFBP pool found primarily in this serum fraction [8, 13-15]. IGFBP-1 is expressed primarily by liver, while IGFBP-2 is expressed in many tissues [15-17]. IGFBP-1 and -2 levels rise with GH deficiency, insulin deficiency, and fasting, and levels fall with GH, insulin, and nutrition therapy; in the case of IGFBP-1, levels are high in neonates with intrauterine growth retardation [15, 18, 19]. Hepatic IGFBP-1 expression is reduced by growth stimulators such as insulin and GH, and is increased by growth-inhibiting

2 344 glucocorticoids [15, 20]. IGFBP-3, the only glycosylated IGFBP, is secreted as forms of approximately 41 and 38 kda by multiple tissues; it is the major serum IGFBP and is the only IGFBP in the 150-kDa serum complex, where it is bound to one IGF molecule and one 90-kDa protein, the acid-labile subunit (ALS) [9, 14, 21]. IGFBP-3 regulation suggests a role as a growth stimulator; levels are low in insulin deficiency, GH deficiency, and fasting, and rise with insulin, GH, and nutrition therapy [9, 21, 22]. IGFBPs 4-6 were recently identified [11, 12] and will not be reviewed in detail. In 1987, it was first proposed that unsaturated IGFBPs might participate in the growth failure of children with CRF [8]. Biological actions of IGFs are mediated through the membrane-bound type I IGF receptor [23]. IGFBPs bind IGFs with affinities similar to those of the type I receptor [24]; thus, excess high-affinity IGFBPs should be able to inhibit IGF action by sequestering IGFs from type I receptors. To be considered growth inhibitors, IGFBPs should meet certain established criteria. The ability of IGFBPs to meet these criteria are considered below. Serum IGFBP levels should be higher in CRF than normal individuals Levels of unsaturated IGFBPs are high in CRF serum; it is these IGFBPs, migrating in the 35-kDa serum fractions, which interfere with IGF assays [7, 8, 25-29]. IGFBP-1 levels are high in CRF serum when measured by radioimmunoassay (RIA), immunoprecipitation, and 125iodine (I)-IGF-I binding [15, 25, 27, 29]. IGFBP-2 levels are also high in CRF serum when measured by RIA, by 125I-IGF-I ligand blot, and by immunoprecipitation of IGFBP-2 crosslinked to lzsi-igf-i [28, 29]. IGFBP-3 levels were not high in CRF serum by xasi-igf ligand blot either with or without immunoprecipitation by IGFBP-3 antisera [29]. Howe+er, IGFBP-3 levels were high in the serum of CRF adults and children when measured by specific RIAs [25-27, 30-32]. In one of these studies, IGFBP-3 was found primarily as fragments in the 35-kDa serum fractions rather than as the usual intact forms at approximately 150 kda [27]. As shown in Fig. 1, multiple IGFBP-3 fragments are present in CRF serum, including an abundant form of approximately 29 kda; these fragments are much less abundant in serum from healthy individuals [33]. Since IGFBP-3 fragments are not detected by 125 I- IGF-I ligand blot, the discrepancy between IGFBP-3 levels in CRF serum as measured by RIA compared with 125I- IGF-I ligand blot was explained. Recent studies analyzed IGFBP-3 forms after size separation of CRF serum on a Sephacryl S-300 column at neutral ph [29], and reached the following conclusions: (1) amounts of intact 41/38-kDa IGFBP-3 forms are equal in CRF and normal sera; (2) intact IGFBP-3 circulates mainly in the 150-kDa fractions of CRF serum; (3) there is no deficiency of this 150-kDa complex in CRF; (4) IGF-I, IGFBP-3, and ALS from CRF sera can all reconstitute a functional 150-kDa complex in vitro; (5) IGFBP-3 fragments are high in CRF serum where they circulate primarily in 35-kDa serum fractions; (6) the high levels of IGFBP-3 fragments in the 35-kDa fractions of Fig. 1. Insulin-like growth factor binding protein-3 (IGFBP-3) forms in chronic renal failure (CRF) sera, Sera from three prepubertal CRF children maintained on peritoneal dialysis were separated by 12% sodium dodecyl sulfate polyacrylamide gel electrophoresis, transferred to nitrocellulose membranes, and then immunoblotted with IGFBP-3g 1 antisera (kindly provided by Dr. Ron Rosenfeld, Oregon Health Science Center, Portland, Oregon, USA) as described previously [33-35]. Molecular weight estimates of IGFBP-3 forms, in kilodaltons (kda), are shown on the right CRF serum can account for the entire increase in IGFBP-3 found in CRF serum. In an attempt to identify specific unsaturated IGFBPs in CRF sera, the 35-kDa CRF serum fractions were affinity cross-linked to lzsi-igf-i and then precipitated with IGFBP-1, -2, or -3 antisera. IGFBP-1, IGFBP-2, and 19- and 14-kDa IGFBP-3 fragments were cross-linked to IGF-I and were more abundant in the 35-kDa fractions of CRF than normal sera [29]. Preliminary studies suggest that serum levels of other IGFBPs may also be high in CRF. High serum IGFBP levels should be related to growth failure High serum levels of IGFBP-1, IGFBP-2, and IGFBP-3 were documented in CRF children with height more than two standard deviations below the mean for age and gender [15, 25, 27, 28, 30-32]. However, since it is likely that CRF children with height in the normal range are also not growing at their full genetic potential [1], it will not be surprising if these children are also found to have high serum IGFBP levels. It is important to remember that IGFBP-3 is the most abundant IGFBP, with mean concentrations of approximately 150 nm in CRF sera [25, 27, 30-32]. IGFBP-2 is also abundant, with mean CRF sera concentrations of approximately 50 nm [28]. In contrast, mean IGFBP-1 levels are relatively low, approximately nm in CRF sera [30, 32]. Thus, on a molar basis, IGFBP-3 and -2 appear more likely to bind IGF-I, and thereby interfere with growth, than IGFBP-1. Therapies which improve growth (such as GH) should lower serum IGFBP levels and/or increase the ratio of serum IGFs/IGFBPs GH therapy of growth-retarded CRF children leads to a marked acceleration of linear growth in association with a rise in serum IGF-I levels [30-32, 36]. IGFBP-1 levels fell a 19 o o

3 345 significantly and convincingly in the two controlled trials of GH therapy in CRF children [30, 32]. This fall correlated with a rise in serum insulin levels (unpublished observations), consistent with the observation that insulin is the major regulator of hepatic IGFBP-1 expression by potently inhibiting IGFBP-1 transcription [15, 20]. When measured by RIA, serum IGFBP-3 levels actually rose in the serum of growth-retarded CRF patients treated with GH [30-32], suggesting that this protein may not be a uremic growth inhibitor. However, Blum et al. [27] noted the high levels of unsaturated IGFBPs in CRF serum, and hypothesized that hepatic IGF-I expression must be quite low or IGF-I would fill these unsaturated sites. This suggests that even normal serum IGFBP-3 levels may be inhibitory if IGF-I expression is decreased, and that this inhibition may be overcome if IGF-I levels rise more than IGFBP-3 levels, thus leading to the concept of IGF-I/ IGFBP-3 ratios. On a molar basis, IGFBP-3 rose much more than IGF-I in the two controlled trials of GH therapy in CRF children [30, 32]. However, when one also considers IGF-II, which: (1) is the major serum IGF on a molar basis; (2) rises with GH therapy in the two controlled studies in CRF children [30, 32]; (3) is a significant mitogen which binds the type I IGF receptor with an affinity close to IGF-I [23], then the molar rise in IGFs is comparable to the rise in IGFBP-3. If one further considers the fall in IGFBP-1 levels with GH therapy, then the IGF/ IGFBP ratio probably rises with GH treatment, compatible with a lower ability of IGFBPs to block IGF action. Ultimately, a ratio of [IGFs]/[IGFBPs with IGF binding affinity >---IGF-I receptor] may better predict the ability of a pool of IGFBPs to impair IGF-mediated growth. Although IGF/ IGFBP ratios are likely a gross oversimplification, they emphasize the need to consider the role of all IGFs and IGFBPs in the growth process. IGFBPs should impair growth in appropriate in vitro models Whole CRF serum was less able than normal serum to stimulate sulfate incorporation into porcine costal cartilage in vitro [27]. If these sera were first passed through an IGF-II affinity column to remove unsaturated IGFBPs, the ability of CRF serum to stimulate sulfate incorporation approached normal, suggesting that unsaturated IGFBPs inhibit the ability of IGFs to act on cartilage [27]. The nature of the unsaturated IGFBPs was not established in this study. When maintained in organ culture, chick embryo pelvic cartilage grows in serum-free medium; basal growth is IGF-I dependent, and exogenous IGF-I can stimulate additional growth. Purified IGFBP-1 markedly inhibited both basal and IGF-l-stimulated growth of this cartilage [37]. Basal growth was inhibited by as little as 0.2 nm IGFBP-1. Since CRF serum contains approximately nm IGFBP-1, and since interstitial IGFBP levels are approximately 10% of serum levels [30, 32, 33, 38], then CRF serum appears to contain sufficient IGFBP-1 to inhibit cartilage growth. IGFBP~2 and IGFBP-3 have not been studied in cartilage models, but each can inhibit IGF-I-stimulated DNA synthesis in cultured fibroblasts [39-42]. In the case of IGFBP-3, inhibition occurs when intact IGFBP-3 is coincubated with IGF-I. Preincubation of fibroblasts with intact IGFBP-3, however, leads to potentiation of IGF-I action [40-42]. The preincubated IGFBP-3 binds to the cells and is processed on the cell surface to lower molecular weight forms with decreased affinity for IGFs; to some extent, potentiation may occur because the low affinity of these cell surface IGFBP-3 fragments allows them to release IGF-I to the IGF-I receptor [41, 42]. No data are available on the ability of soluble IGFBP-3 fragments, such as those present in CRF serum, to modulate IGF-I-stimulated DNA synthesis in cultured fibroblasts. In addition, IGFBP-3 can directly inhibit fibroblast proliferation by mechanisms independent of IGF-I binding [43], but it is unclear whether IGFBP-3 can work through these mechanisms to inhibit cartilage growth. IGFBPs should impair growth in experimental animals Des(1-3)IGF-I, which binds IGFBPs poorly due to the deletion of the 3 amino terminal amino acids, did not stimulate weight gain better than intact IGF-I in mildly uremic rats, but was more efficacious than intact IGF-I in preventing muscle protein degradation. This indirect evidence suggests that, even in early CRF, a slight excess of IGFBPs may inhibit growth-promoting actions of circulating IGF-I [44]. Direct evidence now exists that circulating IGFBPs can impair the growth of nonuremic animals. Treatment of hypophysectomized rats with injections of GH or IGF-I stimulated weight gain and tibial epiphyseal widening, but coinjection of recombinant human IGFBP-1 inhibited this growth in a dose-dependent manner [4]. The injected IGFBP-1 inhibited GH-stimulated tibial epiphyseal widening by >50% in two separate experiments. This IGFBP-1 preparation, which also profoundly inhibited cartilage growth in vitro [37], is nonphosphorylated and thus has a lower affinity for IGFs than all of the phosphorylated IGFBP-1 forms [15, 45]. Although this study provides direct evidence that IGFBP-1 can act as a growth inhibitor, it also suggests that an excess of any unsaturated IGFBP with moderately high affinity for IGF peptides may serve to inhibit GH- or IGF-I-stimulated cartilage growth. In summary, much evidence suggests that excess IGFBPs may inhibit the linear growth of children with CRE IGFBPG meets most of the criteria established for uremic inhibitors, while IGFBP-2 meets some of these criteria. Additional studies are needed to understand the role of IGFBP-3 in this growth inhibition. Ultimately each of these IGFBPs, and perhaps also IGFBPs 4-6, may be found to participate in the growth failure of CRF by contributing to the excess of high-affinity IGFBPs which are a hallmark of the CRF state. Acknowledgements. This work was supported by National Institutes of Health RO1 DK (to D. R. P.).

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Proc Natl Acad Sci USA 88: Literature abstracts Am J Kidney Dis (1995) 26:34-40 Clinical and pathologic features of familial focal segmental glomerulosclerosis Peter J. Conlon, David Butterly, Frank Albers, Roger Rodby, J. Canlie Gunnells, and David N. Howell The occurrence of tbcal segmental glomernlosclerosis (FSGS) in a familial pattern has been rarely reported previously. Over the last 10 years we have treated 31 patients among eight families with familial FSGS. The diagnosis was confirmed by renal biopsy in 18 cases, and each family had at least two members in whom the diagnosis was confirmed histologically. Both males and females were affected, as were both blacks and whites. The mean age at presentation was 28 years, with a range of 8 to 56 years. The mean serum creatinine at presentation was 3.7 mg/dl. Twenty-five of the 31 patients progressed to end-stage renal disease; and treatment with prednisone did not appear to retard the progression to end-stage renal disease. Seven patients received a cadaveric renal transplant and none of them showed evidence of recurrence of disease in the graft. The pattern of inheritance in two families appeared to be autosomal dominant; in the other families the pattern of inheritance was less clear and may have been autosomal recessive, although a familial exposure to an unidentified environmental toxin cannot be excluded. Histologic examination of the renal tissue revealed a variety of changes previously described as occurring in FSGS. We conclude that FSGS may occur in a familial pattern that carries a poor prognosis. Further studies of these families may shed light on the pathogenesis of sporadic FSGS. Am J Kidney Dis (1995) 25: Liddle's syndrome, an underrecognized entity: a report of four cases, including the first report in black individuals Merit F. Gadallah, Kenneth Abreo, and Jack Work Liddle's syndrome, a rare cause of hypokalemic hypertension, is characterized by a renal tubular sodium channel defect resulting in excessive sodium absorption and concomitant potassium wasting. In this disorder, although the clinical manifestations resemble primary aldosteronism, serum and urine aldosterone are suppressed. The syndrome is transmitted in an autosomal dominant pattern. It has been reported previously in white and oriental population but not in the black individuals. We identified four patients (two of whom are black) in our nephrology clinic, with severe hypokalemic hypertension not correctly diagnosed for several years. All patients underwent an extensive work-up for secondary hypertension because of persistent severe hypertension (average blood pressure, 210/130 mmhg) despite high-dose multi-drug therapy. Primary aldosteronism was excluded because of low serum aldosterone. Cushing's syndrome, pheochro- mocytoma, renal artery stenosis, and enzymatic deficiencies of cortisol synthesis (lll~-hydroxylase, 17a-hydroxylase, 5~-reductase, and ll~hydroxysteroid dehydrogenase) were ruled out with extensive endocrine and radiologic studies. Once the diagnosis of Liddle's syndrome was suspected, all patiens were treated with either triamterene or ameloride, with resolution of hypokalemia and correction of hypertension occurring within 5 to 7 days. Our findings suggest that Liddle's syndrome can occur in the black population. Although the actual incidence of this syndrome remains unknown, it may be significantly more common than we are led to believe since it is inherited in a Mendelian pattern. Whether there is a subset of low-renin, salt-sensitive black hypertensive patients who have the same or similar sodium channel defect remains to be elucidated.