11 Growth failure in renal disease

11 Growth failure in renal disease OTTO MEHLS W E R N E R F. BLUM FRANZ SCHAEFER B U R K H A R D TONSHOFF KARL S C H A R E R °.

CLINICAL PRESENTATION Growth pattern Impairment of growth and stunting remains one of the most serious therapeutic problems despite improvement of many treatment modalities in end-stage renal failure in childhood (Holliday et al, 1978; Schfirer et al, 1983; Chesney et al, 1985; Sch~rer and Mehls, 1991). Children often present with an actual height below the third centile of age when chronic renal failure (CRF) is diagnosed. Paradoxically, such children may also have a normal growth velocity (Betts and White, 1976; Schaefer et al, 1992). As a rule, the pattern of growth of children with CRF is influenced by the age of onset of CRF. Growth retardation is more pronounced the earlier renal failure occurs. CRF is related to congenital nephropathies in over 50% of children (Broyer et al, 1981). Children with congenital nephropathies are more seriously affected than individuals in whom renal disease develops later in life. In untreated congenital CRF, a marked retardation of growth can be seen in the first 2 years of life; since normal infants achieve approximately 50% of their growth potential by 2 years of age, CRF may have an important and disproportionate effect on final height. After this age, the growth curve of a child with congenital CRF often parallels normal height centiles (Figure 1). In the last 2-3 years prior to puberty, the height velocity again decreases disproportionately in CRF. The onset of the pubertal growth spurt is delayed and its magnitude depressed, resulting in a further loss of growth potential. It appears therefore, that the height reduction in CRF is mainly the result of growth suppression in two periods; in infancy, when growth is mainly nutrient dependent, and during puberty, when growth is dependent on gonadal hormone in addition to growth hormone (GH). In the primarily GH dependent phase, however, a growth pattern almost parallel to the centiles Baillibre' s Clinical Endocrinology and Metabolism--

Vol. 6, No. 3, July 1992 ISBN 0-7020-1620-9

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Copyright © 1992, by Bailli~re Tindall All rights of reproduction in any form reserved

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for the normal population is observed, even in many children with end-stage CRF. Dialysis Two decades ago, an improvement in the growth of many uraemic patients was seen after the start of long-term haemodialysis (Mehls et al, 1978). In

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retrospect, this was primarily related to the patients who presented with severe malnutrition. Under current conditions, no significant difference is observed between growth before and growth after the start of haemodialysis. On average, growth rate is slightly reduced or, at best, normal. Catch-up growth remains the exception rather than the rule. At the beginning of the 1980s, the introduction of continuous ambulatory peritoneal dialysis (CAPD) brought hope for growth improvement in children with CRF. In peritoneal dialysis, compared with haemodialysis, more uniform detoxification of the body is achieved. In addition, glucose is continuously absorbed from the dialysate, representing approximately 10-15% of the total energy supply (Bonzel et al, 1986). Furthermore, CAPD leads to a significant improvement in renal anaemia (M~ller-Wiefel et al, 1985; Potter et al, 1986). Although preliminary reports gave hope for substantial improvement of growth velocity and final height with CAPD (Stefanidis et al, 1983; Fennell et al, 1984a, 1984b), this could not be confirmed by long-term studies (von Lilien et al, 1989).

Transplantation A well-functioning renal transplant can match the performance of a healthy kidney and provides hope for growth improvement. Unfortunately, only a few children present with catch-up growth after successful renal transplantation (Ingelfinger et al, 1981; Miller et al, 1982; So et al, 1987). The most important inhibitory factors that influence height velocity following renal transplantation are impaired renal function and the immunosuppressive regimen (Ramirez and Fine, 1989). Under immunosuppressive treatment with azathioprine and corticosteroids in prepubertal patients, catch-up growth is only observed when the glomerular filtration rate is nearly normal (Broyer and Guest, 1989). Unfortunately, approximately a quarter of all children with completely normal renal function showed no growth recovery, although the doses of methylprednisolone was - 0 . 4 m g kg -1day -1. A change of daily corticosteroid therapy to alternate-day treatment seems to improve the growth rate (McEnery et al, 1973; Hoda et al, 1975; Broyer et al, 1983; Potter et al, 1975), but prospective studies are missing. Based on a literature survey, Potter (1989) calculated that normal growth can be expected when transplanted children are treated with 6-8 mg/m 2 prednisone on a daily basis or with less than 30 mg/m 2 given every second day. Since 1980, cyclosporin A has been used for immunosuppression. Cyclosporin A treatment allows a general reduction of concomitant corticosteroid medication; thus, an improvement of growth is seen in patients treated with cyclosporin and low-dose corticosteroids (Offner et al, 1987). However, substantial growth retardation and reduced final height persist in the majority of patients (Offner et al, 1987). Promising improvement in growth has been reported after the corticosteroid medication was totally discontinued (Klare et at, 1991), but this procedure can only be tolerated by a proportion of patients without risk of rejection crises.

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Final height

Final adult height in children with CRF has been shown to be considerably lower than the prospective final height predicted at first manifestation of renal failure (Gilli et al, 1985). In the literature, the percentage of patients with a final height below - 2 SD varies from 14% (Gilli et al, 1984) to 77% (Chantler et al, 1981). In 1986, the European Dialysis and Transplant Association (EDTA) published data from 376 young adults, aged 21 years or over, who commenced dialysis before the age of 15 years (Rizzoni et al, 1986). Of these patients 50% had reached a final height below the third centile of the normal population. Children who had continued dialysis until adulthood reached a slightly lower mean final height than children who had received a renal transplant. Among patients who did not reach end-stage renal failure during childhood, the authors observed only a few cases of reduced final height, but less than 25% of these patients achieved a final height above the 50th centile, suggesting that even moderate CRF prevents full exploitation of the genetic growth potential. The EDTA data (Rizzoni et al, 1986) also revealed that boys were more severely affected by uraemic growth failure than were girls. In patients who developed renal failure during childhood, the difference in adult height between the sexes was reduced from 13.1 to 6.5cm. In addition to the differences due to the effects of sex-specific hormones on growth, the higher incidence of congenital nephropathies in boys may contribute to the more marked growth retardation in males. Girls with congenital renal disease remain on average 5 cm smaller than those with acquired disease. This aspect of uraemic growth retardation should be even more significant in the future, since, as a result of improved dialysis in infants and small children, more patients with hereditary nephropathies can be treated and reach adulthood after long phases of severe renal failure.

GROWTH, SKELETAL MATURATION, AND HORMONAL CHANGES DURING PUBERTY IN CRF Growth pattern

In a recent retrospective study of 29 patients with CRF, subnormal pubertal growth was observed in both boys and girls (Schaefer et al, 1990). Boys achieved only 58% and girls 48% of the height gain of similarly latematuring normal children. The minimal height velocity before the pubertal growth spurt was only 45 % of that of late-maturing normal children (Figure 2). Nevertheless, the onset of puberty was delayed by 2.5 years on average. The late onset of puberty allowed an extension of the prepubertal growth phase, resulting in an almost normal late prespurt height ( - 1 standard deviation score (SDS) in boys and +0.1 SDS in girls). Both the minimal growth rate before the spurt and the peak growth rate were significantly reduced; the absolute increase in height velocity was, however, normal. The duration of the pubertal growth spurt was reduced by 1 year in boys and 1.5

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Figure 2. Progressionof the pubertal growth spurt (a) in i5 boys and (b) i4 girls with chronic renal failure (CRF). Height velocitiesare synchronizedaccordingto minimalheight velocity before the pubertal growth spurt (MHV), peak heightvelocity(PHV) and end of the pubertal growth spurt (EHV). The absolute increase in height velocityis PHV-MHV. --, CRF; , normal control; . . . . late maturingcontrol group. Reproducedwith permissionfrom Schaefer et al, 1990.

years in girls. The total pubertal height gain in these patients was only approximately 50% of the growth in normal late-maturing children. At the end of the pubertal growth spurt, the height deficit was - 2 . 9 SD in boys and - 2 . 3 SD respectively in girls. It could also be demonstrated that the degree of renal failure affected the severity of the pubertal growth failure. The most serious growth suppression was seen in patients on dialysis (Schaefer et al, 1989). In patients with renal transplant, peak height velocity SDS was inversely correlated with the cumulative amount of steroids received during the year of the growth spurt peak (Schaefer et al, 1990). Skeletal maturation

Analysis of the pubertal growth spurt and skeletal maturation of the patients described above revealed that the bone age at the onset of the pubertal growth spurt was retarded by an average of 2.9 years in boys and 1.3 years in girls (Schaefer et al, 1990). However, the variation in bone age at the start of the spurt was even larger than the variation in chronological age. During puberty, the variability of bone age decreased with advancing maturation. On the assumption that bone age in normal children generally corresponds to chronological age, peak height velocity and so-called endheight velocity (= 1 cm/year) appear to occur at earlier stages of skeletal maturation in patients with CRF (Schaefer et al, 1989).

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Preliminary results from the ongoing prospective cooperative study of pubertal development in CRF (Schaefer et al, 1992) show that skeletal maturation accelerates markedly during pubertal development in individual patients, whereas progressive retardation of bone age may occur in other patients, despite pubertal growth acceleration and sexual maturation. Further studies are needed to identify the causes for the different patterns of bone maturation. The degree of uraemia and the treatment modalities may have significant influence.

Hormonal changes During the normal pubertal growth spurt, a persistent activation of the hypothalamo-pituitary-gonadal axis and a transient augmentation of GH secretion is seen. In pubertal children with CRF, increased concentrations of luteinizing hormone (LH) and follicle stimulating hormone (FSH) are found before and during puberty (Ferraris et al, 1980; Roger et al, 1981; Oertd et al, 1983). Early investigations of prepubertal and pubertal boys with CRF revealed reduced testosterone serum concentrations (Ferraris et al, 1980; Oertel et al, 1983). Subnormal plasma oestrogen levels have been found in prepubertal girls with CRF by several investigators (Lira et al, 1978; Ferraris et al, 1987). An inverse correlation was found between serum creatinine levels and oestradiol concentrations in patients with preterminal renal failure and those with renal transplants. Serum oestrogen concentration was lowest in girls on haemodialysis. Longitudinal analyses revealed an insufficient increase of oestradiol concentration during puberty in patients with deteriorating renal function, whereas successful renal transplantation was able to induce an increase in the serum concentration (Ferraris et al, 1987). Consequently, a combination of raised gonadotrophin levels and low concentrations of gonadal hormone suggested a partially compensated hypergonadotrophic hypogonadism due to primary gonadal failure (Rauh and Oertel, 1984). In contrast, recent investigations point to a functional dysregulation of the hormones in the reproductive axis. Preliminary results from the cooperative study group on the pubertal development in CRF demonstrated a late onset of nocturnal pulsatile secretion of LH, suggesting a functional dysregulation of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator (Schaefer et al, 1991a). Supporting this concept, a recent analysis of LH concentration profiles by the deconvolution method (Schaefer et al, 1991b) revealed marked pituitary hyposecretion of LH. According to these investigations, the normal or elevated plasma levels of LH in CRF result from a decreased metabolic clearance of LH because of impaired renal function. Consequently, the decreased metabolic clearance of LH may mask reduced hypothalamo-pituitary activity and may thus prevent understimulation of the gonads. However, since FSH levels remain high in some patients after normalization of renal function by renal transplantation, irreversible damage to the germinal epithelium by uraemia is not excluded. As will be discussed later, GH serum concentration is increased in uraemia, particularly in patients on dialysis (El Bishti et al, 1978; Mehls et

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al, 1990). A cross-sectional study on plasma GH concentration profiles gives evidence that the increase in mean plasma GH concentration during puberty is the consequence of an amplitude modulated, augmentation of pulsatile GH secretion (Schaefer et al, 1991c). The physiological transient increase in GH pulse amplitude during puberty is also seen in patients with CRF (Schaefer et al, 1991c). A positive correlation between the mean GH levels and the plasma testosterone concentration was observed in patients with preterminal renal failure, but not in patients on dialysis. In contrast, GH secretion did not differ between pubertal stages I and III in patients given a renal transplant, and the characteristics of GH secretion were not correlated with circulating testosterone concentrations. Peak GH amplitudes and mean levels were correlated with the actual growth rate in transplant recipients, but not in uraemic patients with preterminal renal failure or on dialysis. In children with renal allografts, an inverse relationship between the cumulative dose of corticosteroids and the GH peak amplitude was observed (Schaefer et al, 1990). Synopsis

Based on the presented information, the following hypothesis can be made (Schaefer et al, 1992). Gonadal hormone concentrations increase during puberty in almost all patients. In patients with preterminal renal failure and in patients with functioning renal allografts, the somatotroph responsiveness to stimulation by gonadal steroids appears to be conserved. However, in patients on dialysis the association between gonadal hormone levels and GH peak levels is lacking. In these patients, the lack of correlation between GH concentration and growth rates suggests end-organ hyporesponsiveness to GH, and the growth promoting effect of GH may be insufficient, although transient stimulation of GH secretion is observed during puberty. InAransplanted children, growth rates are positively correlated with the amplitude of GH pulses (El Bishti et al, 1978), but the pubertal increase in GH pulse amplitudes is blunted because corticosteroid treatment negatively affects endogenous GH secretion. The insufficient action of GH contrasts with a normal sensitivity to the direct stimulatory effect of gonadal steroids on epiphyseal growth and bone maturation (Jones et al, 1980). The combined action of both hormonal systems results in a pubertal growth spurt which is characterized by diminished peak height velocity and duration but a normal absolute increase in growth rate. This means that GH resistance which is already seen in prepubertal children (see below) continues during puberty. The combination of insufficient GH dependent growth with progressive epiphyseal maturation during puberty leads to irreversible loss of growth potential. RESISTANCE TO GH IN URAEMIA GH secretion

Basal levels of serum GH are elevated in uraemic children, depending on the extent of renal failure (Davidson et al, 1976; Samaan and Freeman, 1970).

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Conventional stimulation tests led to a sustained exaggerated increase in serum GH concentration. Therefore, it has been thought in the past that G H plays no role in the pathophysiology of growth disorders associated with CRF. Also, the rapid decrease of plasma concentration of G H after administration of GH-releasing inhibiting hormone (GHRIH) (Bessarione et al, 1987) was taken as evidence for an intact pituitary which secretes large amounts of GH. Interpretation of serum G H concentration for secretion rate is not possible because the metabolic clearance rate of GH is reduced in uraemia (Pimstone et al, 1975), as is the clearance rate for most peptide hormones, including LH/FSH and prolactin. Recently, deconvolution analysis has permitted indirect calculation of pituitary GH secretion, independent of the knowledge of the metabolic clearance rate of the hormone. The investigations have provided evidence of normal spontaneous nocturnal G H secretion in uraemia at clearly raised, integrated serum concentrations (T6nshoff et al, 1991c). By the same analysis, a much longer G H half-life was observed in dialysed children in comparison with a control group (38.9 + 11.2 versus 19.2 + 14.4 rain). This explains the increase in basal G H levels as well as in peak amplitude.

GH binding protein (GH-BP) Approximately 50% of circulating GH is bound to two different plasma proteins (Herington et al, 1991). The physiological relevance of the GH-BPs is not well understood. There is good evidence that the high affinity GH-BP represents the extracellular domain of the hepatic GH receptor (Baumann et al, 1986; Leung et al, 1987; Carlsson et al, 1991). Decreased activity of GH-BP in the serum of uraemic children was found (Postel-Vinay et al, 1991). The decrease was more pronounced in dialysed children than in children in early stages of renal failure. There is evidence from animal experiments that the expression of the G H receptor is reduced in liver cells in uraemia (Finidori et al, 1980). Whereas GH-BP increases in children with hypopituitarism under recombinant human GH (rhGH) treatment (Fontoura et al, 1991), such an increase was not seen in children with CRF up to 1.5 years after the start of therapy. According to this finding, it seems that reduced expression of GH receptor may be one of the possible reasons for GH resistance in uraemia.

Insulin-binding growth factors (IGFs) and IGF-binding proteins (IGFBPs) The growth-promoting action of GH is at least in part mediated by IGF-I produced locally (D'Ercole et al, 1984; Isgaard et al, 1988) or in the liver (Roberts et al, 1986; Hynes et al, 1987), which is the main source of circulating IGFs (Schwander et al, 1983). A second major regulator of IGF-I synthesis is the nutritional status (Clemmons et al, 1981; Islcy et al, 1983), both in hepatic and non-hepatic tissues (Straus and Takemoto, 1990). The relevant dietary factors are both protein and calorie intake. Below an intake of 12 kcal kg -1 day -1 an insensitivity to G H is observed (Isley et al, 1984),

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which may be due to a decrease of G H receptor density in the liver or to postreceptor mechanisms (Straus and Takemoto, 1990; Thissen et al, 1991). The stimulatory effect of sex steroids on IGF-I serum levels seems to be mediated through an increase of GH secretion (Parker et al, 1984; Rosenfield and Furlanetto, 1985)i Corticosteroids were found to have little influence on IGF-I levels (Miell et al, 1991), although in vitro cortisol had a suppressing effect on IGF-I secretion by osteoblasts (McCarthy et al, 1990), suggesting a possible local effect. The regulation and physiological significance of IGF-II is still less clear. Both increased and decreased concentrations of IGF-I and IGF-II were reported in CRF (reviewed in Powell et al, 1989). The different results are explained by the interference of elevated concentrations of IGFBPs. When special care was taken to exclude these technical problems, IGF-I was found to be normal or slightly decreased and IGF-II was normal or slightly increased (Powell et al, 1986, 1987, 1989; Blum et al, 1991). In contrast, several assays have revealed reduced IGF-I bioactivity in uraemia, even after correction for increased serum sulphate concentration (Phillips and Kopple, 1981; Blum et al, 1991). IGF bioactivity is lower in patients on haemodialysis than in preterminal CRF but increases after successful renal transplantation (Saenger et al, 1974). The discrepancy between the normal concentrations of IGF-I and IGF-II and the reduced IGF bioactivity in uraemia suggests the presence of IGF inhibitors. Although low molecular weight (about 1 kDa) inhibitors have been reported (Phillips et al, 1984), their structural characterization is still awaited. Large molecular weight inhibitors were identified, and there is good evidence that these inhibitory polypeptides are related to IGFBPs (Ooi and Herington, 1990; Blum et al, 1991). To date, at least six classes of IGFBPs can be distinguished on the basis of their primary structure (Brewer et al, 1988; Brinkmann et al, 1988; Wood et al, 1988; Mohan et al, 1989). The molecular weights of these proteins vary between 24 and 42 kDa. IGFBP-3 is the most abundant binding protein in the circulation, carrying about 90% of the IGFs. It has the unique property of associating with an acid-labile subunit after binding of either IGF-I or IGF-II, thus forming a large molecular weight complex (120-150kDa) (Baxter and Martin, 1989), which is no longer filtered by the kidney. The serum concentrations of the various IGFBPs are regulated by different factors: IGFBP-1 is suppressed by insulin (Suikkari et al, 1989) and IGFBP3 is increased by G H (Baxter and Martin, 1986; Blum et al, 1990; Blum and Ranke, 1991). The specific regulation o f the other IGFBPs is less clear. In kidney disease, renal function becomes an additional determinant. A significant negative correlation is seen between the fall of glomerular filtration rate and the increase of IGFBP-1, IGFBP-2 and IGFBP-3 serum levels (T6nshoff, 1992; O. Mehls, unpublished data). In end-stage renal failure, IGFBP levels are markedly elevated (Blum et al, 1989; Lee et al, 1989; T6nshoff, 1990a; Blum, 1991a). This elevation is due to the accumulation of small IGFBP forms with a molecular weight of less than 60 kDa, in particular to free IGFBP-3 and IGFBP-3 related fragments (Blum et al, 1991) (Figure 3) which are normally cleared from the circulation by the

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kidneys. It is of note that these fragments are still able to bind IGFs. In healthy subjects, the total concentration of IGFs is linearly related to IGFBP-3, while the concentration of IGF-I shows an exponential relationship. In contrast, in uraemia there is a marked excess of IGFBPs over IGFs (Figure 4), resulting in a marked increase of free IGF-binding capacity (Figure 5) (Goldberg et al, 1982; Powell et al, 1987; Blum et al, 1991). As a consequence, free IGF must be reduced in chemical equilibrium. Removal of the free IGF-binding capacity by affinity chromatography results in an increase of IGF bioactivity, suggesting that the excess of IGFBPs acts as an IGF inhibitor (Blum et al, 1991). Under normal conditions, increased free IGF-binding capacity would

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immediately be saturated by IGFs produced in the liver. This would result in raised serum concentrations of IGF-I and IGF-II. In uraemia, however, no raise is noted, suggesting that IGF production is reduced. This concept is supported by estimation of IGF secretion rates using a mathematical model (Blum, 1991). Consequently, the reduced serum concentration of free IGF-I and the reduced IGF bioactivity result from diminished IGF-I production as well as from excess IGFBP-3. Since IGF-I synthesis is directly regulated by GH, a diminished secretion rate suggests relative GH insensitivity in uraemia. One possible mechanism, among others, could be a decrease in GH receptor density in the liver, as discussed above. These findings raise the question of whether low concentrations of free IGF-I are a major cause for growth retardation. Support for this concept comes from clinical trials of GH treatment in children with CRF. In these patients, a rise of IGF-I serum concentration out of proportion to the rise of IGFBP-3 concentration is noted (Mehls et al, 1990; T6nshoff et al, 1990a). At the same moment, IGF-I bioactivity in the uraemic serum normalizes.

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THERAPY Conservative treatment

A combination of several factors, not only resistance to GH, is generally responsible for impaired growth in CRF (Mehls et al, 1978; Sch~irer and Gilli, 1984). The patient's age, the type, duration and severity of renal disease, the treatment used and the patient's social environment all play important roles. Furthermore, protein and energy deficiency, disturbance of water and electrolyte metabolism, acidosis, renal osteodystrophy and renal anaemia have been identified as contributing factors for growth impairment. Consequently, a number of therapeutic manoeuvres are necessary to compensate for these factors (Chantier, 1992). Metabolic acidosis must always be treated to reduce catabolism (Kleinknecht et al, 1983; Rodriguez-Soriano et al, 1986). Adequate nutrition is of paramount importance during the first 1-2 years of life because growth in this age group is mainly dependent on food intake, as pointed out earlier. Later on, energy intake must be adequate (70 kcal kg -1 day -1) to prevent catabolic situations, but higher intakes do not lead to catch-up growth (Arnold et al, 1983). The development of secondary hyperparathyroidism, renal osteodystrophy and reduced pancreatic B-cell function can be prevented by prophylactic administration of small doses of 1,25-dihydroxyvitamin D3 in the early stages of chronic renal failure. Early treatment of renal anaemia with recombinant erythropoietin has no significant effect on growth (Schaefer et al, 1991d) or cardiac function, physical activity and the appetite of the patients. The effect is evidenced by the fact that start of dialysis can be postponed in many patients. Disappointingly, none of these treatment modalities resulted in a meaningful improvement in height in the majority of patients. Nevertheless, optimal conservative treatment is a precondition for positive therapeutic effects with new treatment modalities. Hormonal treatment

Growth hormone is the major determinant for growth during the prepubertal phase after the second year of life. Since there is resistance to GH in CRF, which can be overcome by large amounts of GH, rhGH seems to be an ideal treatment modality for uraemic growth failure. Resistance to G H probably persists during puberty as sex steroids display their normal effects on growth and bone maturation. Consequently, rhGH also seems to be an ideal treatment modality in this age group, but there is concern as to whether it induces early puberty, shortens the duration of puberty, and accelerates bone maturation (T6nshoff et al, 1990b, 1991b). There are no data available at this moment but, if this reasoning is correct, one would have to consider the possibility of continuing rhGH treatment in prepubertal and pubertal children, at the same time postponing the onset of puberty by G n R H analogue treatment to achieve optimal final height. In renal allograft recipients, glucocorticosteroids reduce the food

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efficiency ratio, i.e. weight gain per food intake, as shown in animal studies (Kovhcs et al, 1991), and reduce endogenous GH secretion (Pantelakis et al, 1972; Schaefer et al, 1991c). In this way, the administration of rhGH serves as a form of replacement therapy for children with steroid induced G H hyposecretion. It also corrects the food efficiency ratio (Kovhcs et al, 1991). However, rhGH may also counterbalance the immunosuppressive effects of glucocorticosteroids to a certain extent. Clinical results of rhGH treatment

After it had been shown that exogenous rhGH improved growth in uraemic animals (Mehls et al, 1988), many clinical trials were started (Koch et al, 1989; Rees et al, 1990; T6nshoff et al, 1990a, 1991b, 1992; Fine et al, 1991a,b). There are currently extended data for 2 year results and anecdotal observations up to 5 years. There is no doubt that rhGH is effective in improving growth. In prepubertal children, growth rate is more than doubled during the first year of treatment when compared .with growth velocity during the year prior to therapy. During the second treatment year, growth velocity is somewhat less than during the first year, but still significantly higher than before treatment (Figure 6). In our experience, the mean change in height SDS within 2 years was + 1.5 SDS. Placebo controlled trials confirm these tremendous effects. In the Dutch study (Hokken-Koelega et al, 1991), 6 months on and 6 months off therapy intervals were compared, whereas the design of an ongoing American study compares rhGH treated and placebo treated patients over a period of 2 years, after randomization. The effects of rhGH during puberty are more difficult to evaluate, since differentiation from the endogenous growth spurt is not always possible. Before more exact analyses can be done, we need more information on the natural course of bone maturation in children with CRF without hormonal treatment. Prepubertal children with renal allografts generally respond in the same way as children before renal transplantation (Fine et al, 1991a; T6nshoff et al, 1991b; van Es et al, 1991). It is of interest to note that many transplanted children with normal glomerular filtration rates who do not grow sufficiently respond well to rhGH, thus confirming that the growth depressing effects of corticosteroids can be overcome by rhGH. The nUmber of rejection crises under rhGH treatment was 10 per 1600 patient-treatment months. The frequency is not out of proportion to that seen in non-rhGH treated allograft recipients; however, it does not exclude the possibility that the rejection crisis in one patient was triggered by rhGH. Most investigators treated their patients with a dose of 28-30 units m-Z week- I or i unit kg - 1 week- 1by daily injection. There is a wide variation of growth response from one patient to another. Some patients starting below - 2 SD for height reached their target centile after 2-3 years of treatment, whereas others responded very poorly. Anecdotal reports show that doubling of rhGH doses may improve growth in the poor responders (unpublished communication). T h e reasons for these discrepancies are not entirely clear.

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Some, but certainly not all determinants are the degree of stunting and the height velocity before start of treatment. Short patients who have a relatively normal growth velocity during the year before treatment seem to respond best (Hokken-Koelega et al, 1991). If a patient has reached his or her target centile, one might consider terminating rhGH treatment but one has to be aware that height velocity may decrease dramatically following this procedure. It is probably safer to treat those patients throughout puberty until final height is reached. SUMMARY

Children with congenital CRF lose height potential mainly during two distinct growth periods; infancy and puberty. The onset of puberty is late, the pubertal growth spurt starts from a very low rate of growth velocity, and peak height velocity is lower than normal although the absolute increment of height velocity is comparable to the increment in normal children. Furthermore, the duration of pubertal growth spurt is reduced in CRF. During infancy and early childhood, malnutrition, electrolyte disturbances and metabolic acidosis are the main contributing factors for reduced growth, whereas hormonal disturbances are responsible for growth impairment during puberty. There is evidence for resistance to growth hormone in CRF, which starts in early childhood and persists until the end of puberty. Growth hormone secretion is normal in CRF, but GH half-life is prolonged. The binding activity of the stable growth hormone binding protein is reduced, which points to a low receptor expression in the liver. Hepatic IGF-I production is diminished. However, the serum concentration of IGF binding proteins (IGFBP) is increased due to reduced renal filtration of low molecular weight subunits of IGFBP. Mainly, the accumulation of IGFBP-3 leads to increased IGF-binding capacity of the uraemic serum. Both, reduced IGF-I production and increased binding of IGF to IGFBP-3 result in decreased IGF bioactivity. During infancy, loss of growth potential can be prevented by adequate nutrition. Later in life, catch-up growth cannot be induced by nutritional intervention or dialysis. Renal transplantation allows catch-up growth in only a small percentage of patients. Treatment with one IU rhGH/kg/week improves growth velocity and growth in all stages of renal disease. The mean increment of height in prepubertal children is +1.5 SDS within two treatment years. The effect of rhGH during puberty as well as the effect on final height remain to be determined. REFERENCES

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