Bone density and body composition in chronic renal failure: effects of growth hormone treatment

Metabolic bone disease and growth retardation are common complications of chronic renal failure (CRF). We evaluated bone mineral density (BMD), bone metabolism, body composition and growth in children with CRF, and the effect of growth hormone treatment (GHRx) on these variables. Thirty-three prepubertal patients with CRF were enrolled including 18 children with growth retardation, who were treated with growth hormone for 2 years. Every 6 months, BMD of lumbar spine and total body, and body composition were measured by dual-energy X-ray absorptiometry. Biochemical parameters of bone turnover were assessed. Mean BMD of children with CRF did not differ from normal. During GHRx, BMD and bone mineral apparent density of lumbar spine and height SDS increased, whereas BMD of total body did not change. Lean body mass increased in the GH group. Alkaline phosphatase increased significantly in the GH group only. The other biochemical parameters of bone turnover increased in both groups, none of them correlated with the changes in BMD. No serious adverse effects of GHRx were reported. In conclusion, BMD of children with CRF did not differ from healthy children. Adequate treatment with α-calcidiol or the short duration of renal failure may have attributed to the absence of osteopenia in our patients. BMD of the axial skeleton and growth improved with GHRx. Received: 18 April 2000 / Revised: 26 June 2000 / Accepted: 29 June 2000     

Somatostatinergic tone in children on chronic haemodialysis and after renal transplantation

The role of somatostatinergic tone (SST) in growth hormone (GH) neuroregulation in children with chronic renal failure (CRF) and short stature (mean height standard deviation score –3.47) was investigated. Ten children (9 males, 1 female), mean age 13.4 years (range 8–17 years), five with renal transplants (TP) and five on chronic haemodialysis (HD), underwent three separate investigations: (1) measurement of spontaneous GH secretion; (2) measurement of GH after infusion of GH releasing hormone (GHRH); (3) measurement of GH following treatment with pyridostigmine bromide (PD) and subsequent infusion of GHRH. All patients showed normal or exaggerated spontaneous nocturnal GH secretion (mean concentration values ranging between 3.8 and 19.07 ng/ml). In four of ten patients GHRH was not able to cause an increase in GH levels (mean peak GH 7.35±2.05 ng/ml) while PD pretreatment reinstated the GH response to GHRH (mean peak GH 55.25±17.23 ng/ml) in these children. In the other patients in whom GHRH-induced GH release was normal or exaggerated (mean peak GH 42.0±13.8 ng/ml), PD did not potentiate the GH response to GHRH (mean peak GH 54.83±7.88 ng/ml). These different types of responses were observed both in TP and HD patients. Our data indicate that: (1) PD potentiates the response to GHRH only when GHRH alone is not able to cause GH release, suggesting that SST is already reduced in patients with a normal or exaggerated GH response to GHRH; (2) in CRF patients the SST can be either reduced or increased, at least during the daytime.     

The effect of growth hormone on the growth failure of chronic renal failure

To investigate the effects of growth hormone (GH) on the reversal of growth failure in uremia, recombinant human GH (rhGH) was administered to rats with chronic renal failure (CRF). The dosage of rhGH was 3 IU/day (i.p.) for 13 days after the induction of CRF by 5/6 nephrectomy. Animals were classified into four groups: untreated nephrectomized rats (NX,n=40), GH-treated nephrectomized rats (NX+GH,n=18), sham-operated rats fed ad libitum (SHAMAL,n=27), and sham-operated rats pair-fed with 10 NX rats (SHAMPF,n=10). NX and NX+GH rats developed a similar and moderate degree of CRF, serum urea nitrogen being (mean±SEM) 49±3 and 54±4 mg/dl, respectively, compared with 16±4 and 19±0 mg/dl in SHAMAL and SHAMPF groups. Weight (56.0±3.3 g) and length (3.5±0.1 cm) gains of NX rats were lower than those of SHAMAL rats (94.2±4.0 g,P<-0.0001 and 4.1±0.2 cm,P<-0.01). Growth of the SHAMPF group and the matched NX rats was not significantly different. Weight (56.2±5.0 g) and length (3.4±0.2 cm) gains of NX+GH and NX rats were similar, the beneficial effect of GH therapy on growth being observed in only those animals with more severe degrees of uremia. This growth-promoting action resulted from greater food efficiency and not from stimulated food intake. The hypercholesterolemia seen in NX rats, 81±2 mg/dl versus 55±3 mg/dl in SHAMAL (P0.0001), was not increased in the NX+GH group, 87±3 mg/dl. There was a positive and significant correlation between serum cholesterol and serum urea nitrogen values in NX and NX+GH animals. This study suggests that growth impairment of mild CRF is mainly due to malnutrition and is refractory to GH administration. GH therapy improves the growth rate of animals with advanced CRF without aggravating their lipid abnormalities.     

Effects of growth hormone administration in pediatric renal allograft recipients

The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2±2.0 years) all of whom had bone ages less than or equal to 12 years (10.0±1.4 years), a height standard deviation score of less than –2.5 (–4.9±1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40ml/min per 1.73 m² (51±6.8 ml/min per 1.73 m²), and stable renal function on alternate-day prednisone (16.7±2.6 mg/m² per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5±1.6 cm/year pre therapy, 8.5±1.4 cm/year post therapy,P<0.001) and percentage of expected growth velocity for bone age (67±31% pre therapy, 163±27% post therapy,P<0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH. The potential risk of deterioration in renal function due to rGH-induced hyperfiltration must be investigated.     

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     

Growth charts for prepubertal children with chronic renal failure due to congenital renal disorders

Despite the high prevalence of and therapeutic attention to growth failure in children with chronic renal failure (CRF), systematic evaluation of spontaneous growth in CRF are lacking. Therefore, we collected retrospectively longitudinal growth and biochemical data in 321 prepubertal patients treated for CRF due to congenital renal disorders. Data were recorded at 3-month intervals during the first 2 years of life and 6-monthly thereafter, up to the age of 10 years. Around 100 measurements were available per age interval. Mixed-longitudinal percentile curves of height and height velocity were constructed. Moreover, a statistical comparison with the heights and height velocities of healthy children and an evaluation of the effect of biochemical parameters on growth was performed. The CRF children had normal heights at birth but dropped below the 3rd normal percentile during the first 15 months of life. Thereafter, growth patterns usually were percentile parallel, with a mean height standard deviation score (SDS) of –2.37±1.6. Height velocities were consistently lower in patients with glomerular filtration rates (GFRs) below onethird of the lower normal limit (25 ml/min per 1.73 m² for patients >1 year) than in patients with better renal function. This difference in growth rates resulted in a mean height SDS of –1.65±1.5 SDS and –2.79±1.4 SDS (age 1–10 years) in the subgroups with relatively better and worse GFR, respectively. Regression analysis confirmed that GRF was a weak but significant predictor of height velocity SDS in most age groups.Study group members: I. Rätsch (Ancona), K. Michelis, T. Kapogiannis (Athens), F. Jung, T. Lennert (Berlin I), S. Gellert (Berlin II), T. Tulassay, P. Sallay (Budapest), T. von Lilien, D. Michalk (Cologne), M.-A. von Wendt-Göknur (Erlangen), K. E. Bonzel (Essen), R. Gusmano, E. Verrina (Genova), G. Offner (Hannover), O. Mehls, A.-M. Wingen, C. Fabian-Bach (Heidelberg, coordinators), A. Appiani, A. Bettinelli (Milan), J. Feber (Prague), G. Rizzoni, S. Picca (Rome), H. J. Stolpe, M. Wigger (Rostock), J. Kist-van Holthe, E. Wolff (Rotterdam, coordinators for the centers Amsterdam, Antwerp, Groningen, Nijmegen, Rotterdam), U. Berg (Stockholm), M. Fischbach (Strasbourg), E. Dobos (Szeged), E. Balzar (Vienna), T. Neuhaus (Zurich).     

Post graft development of short children treated with growth hormone before kidney graft

Sixteen prepubertal patients with chronic renal failure (CRF) were given daily recombinant human growth hormone (rhGH) treatment (1.2 IU/kg per week) for 2.6±1.6 years until kidney transplant. Therapy was then discontinued and the patients followed for a further 3.5±1.4 years. During treatment, mean height increased from –3.0±0.9 standard deviation score (SDS) to –1.9±1.4 SDS (P<0.001) at the time of transplantation, corresponding to a mean height gain of +1.2±0.9 SDS. After discontinuation of rhGH therapy, prepubertal children continued a partial catch-up growth with a height gain of +0.5±0.8 SDS for the follow-up period. Conversely, negative changes of height were observed in pubertal transplanted children: –0.5±0.4 SDS in patients grafted at early stages of puberty (P2–P3) and –0.15±0.9 SDS in patients grafted at late stages of puberty (P4–P5). These data confirmed the benefit of rhGH therapy in CRF patients. Nevertheless, only early initiation of rhGH treatment led some of these patients to their target height at transplantation, thus preserving their potential growth. Reinitiation of rhGH therapy after transplantation should be considered in order to complete catch-up growth to target height in prepubertal children. Received: 23 July 1998 / Revised: 8 December 1998 / Accepted: 13 December 1998     

Recombinant human growth hormone treatment of children with chronic renal failure: long-term (1- to 3-year) outcome

Treatment of nine boys, aged 2.8–16.3 years, with growth retardation consequent to chronic renal failure (CRF), with recombinant human growth hormone (rhGH) for 12–36 months demonstrated a significant improvement in growth velocity at each 12-month interval compared with that achieved the year prior to treatment. Despite the acceleration in growth velocity the bone age did not increase more than the increase in chronological age during the period of treatment. The mean calculated creatinine clearance did not decrease significantly during the 36 months of treatment; however, two patients required institution of dialysis at 18 and 30 months following the initiation of rhGH treatment. There was no exacerbation of the glucose intolerance of uremia following rhGH treatment. Currently, six of seven patients who have been treated for more than 24 months have achieved sufficient acceleration of growth velocity to attain a standard deviation score that was more positive than –2.00, and are above the 5th per centile for chronological age on the growth curve. These data indicate that rhGH treatment of growthretarded children with CRF results in accelerated growth velocity during the 2nd and 3rd years of treatment, and demonstrate the potential for such children to achieve normal stature for chronological age despite the continued presence of renal failure.     

Effects of growth hormone on growth factors after renal transplantation

Growth retardation occurs frequently in renal transplanted children (RTx) and can be improved by growth hormone (GH) treatment. This study retrospectively examines the insulin-like growth factor-1 (IGF-1) and IGF binding protein (IGFBP) profile of ten growth-retarded children previously given renal allografts, after 1 year of GH treatment period. Ten prepubertal patients (nine boys and one girl) were investigated. They had a mean chronological age (CA) of 11.4±1.1 years and a mean bone age (BA) of 7.3±0.9 years. Mean height was –3.9±0.4 SD units below the mean for CA. The mean body mass index (BMI) was 16.9±0.6 and the mean inulin clearance was 36.5±4.9 ml/min/1.73 m². Recombinant hGH was given at 4 IU/m²/day. Plasma GH, total and free IGF-1, IGFBP-2 and -3 were measured by specific radioimmunoassay (RIA). IGFBPs were characterized by SDS PAGE techniques and ligand and immunoblot analyses. Mean velocity was markedly increased (P<0.01) after 1 year of GH therapy, expressed as SD score for BA. The range of growth response was wide. The total and free plasma IGF-1 increased (P<0.01) by about 100% (mean values after GH therapy: 95.9± 2.1 nM and 165±29 pM, respectively). Plasma IGFBP-3 concentrations increased by about 40% (mean value: 148±18 pM, P<0.01), with a concomitant increase in both intact IGFBP-3 and its 30-kDa proteolytic fragment. There was no change in plasma IGFBP-2 concentration. Both mean values of inulin clearance and BMI were unchanged during the treatment. In view of the IGF-1/IGFBP concentration changes, there should have been an even better growth response to GH therapy in these patients. This strongly suggests IGF-1 insensitivity, probably as a result of corticosteroid therapy. Received: 12 April 2000 / Revised: 31 July 2000 / Accepted: 1 August 2000     

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.     

Growth hormone/insulin-like growth factor system in children with chronic renal failure

Disturbances of the somatotropic hormone axis play an important pathogenic role in growth retardation and catabolism in children with chronic renal failure (CRF). The apparent discrepancy between normal or elevated growth hormone (GH) levels and diminished longitudinal growth in CRF has led to the concept of GH insensitivity, which is caused by multiple alterations in the distal components of the somatotropic hormone axis. Serum levels of IGF-I and IGF-II are normal in preterminal CRF, while in end-stage renal disease (ESRD) IGF-I levels are slightly decreased and IGF-II levels slightly increased. In view of the prevailing elevated GH levels in ESRD, these serum IGF-I levels appear inadequately low. Indeed, there is both clinical and experimental evidence for decreased hepatic production of IGF-I in CRF. This hepatic insensitivity to the action of GH may be partly the consequence of reduced GH receptor expression in liver tissue and partly a consequence of disturbed GH receptor signaling. The actions and metabolism of IGFs are modulated by specific high-affinity IGFBPs. CRF serum has an IGF-binding capacity that is increased by seven- to tenfold, leading to decreased IGF bioactivity of CRF serum despite normal total IGF levels. Serum levels of intact IGFBP-1, -2, -4, -6 and low molecular weight fragments of IGFBP-3 are elevated in CRF serum in relation to the degree of renal dysfunction, whereas serum levels of intact IGFBP-3 are normal. Levels of immunoreactive IGFBP-5 are not altered in CRF serum, but the majority of IGFBP-5 is fragmented. Decreased renal filtration and increased hepatic production of IGFBP-1 and -2 both contribute to high levels of serum IGFBP. Experimental and clinical evidence suggests that these excessive high-affinity IGFBPs in CRF serum inhibit IGF action in growth plate chondrocytes by competition with the type 1 IGF receptor for IGF binding. These data indicate that growth failure in CRF is mainly due to functional IGF deficiency. Combined therapy with rhGH and rhIGF-I is therefore a logical approach.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     

Intraperitoneal administration of recombinant human growth hormone in children with end-stage renal disease

Recombinant human growth hormone (GH) therapy has been shown to be effective in the treatment of growth failure related to growth hormone resistance among children with chronic renal failure. The traditional route of administration is subcutaneous injection. This study was designed to evaluate the effectiveness and tolerability of intraperitoneal (IP) administration of GH in prepubertal peritoneal dialysis patients. Nine subjects were enrolled. Eight completed 24 months of therapy with GH. Baseline height standard deviation scores (SDS) and growth velocity for the prior year were used for comparison. Peak serum GH was achieved 4 h after administration and serum half-life was 4.6 h. Mean height SDS was –3.1 at baseline, –2.5 at 1 year, and –2.3 at 2 years (NS) of GH therapy. Mean height velocity increased from a baseline of 4.6 cm/yr to 8.5 cm/yr in year 1 (P<0.05) and 6.1 cm/yr in year 2 (NS) of IP GH therapy. Peritonitis infection rates were not increased from overall center rates. This research suggests that the intraperitoneal route of administration of GH can be utilized in the treatment of short stature among children requiring maintenance peritoneal dialysis therapy. Received: 8 February 1999 / Revised: 24 May 2000 / Accepted: 25 May 2000     

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     

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.     

Factors influencing the response to growth hormone in children with renal disease

The effects of age, height velocity over the preceding year, glomerular filtration rate (GFR) and prednisolone dose on growth response have been assessed by single and multiple linear regression analysis in 23 prepubertal children [age, mean (SD), 8.2 (2.5) years] with chronic renal failure (CRF) and 16 prepubertal children [12.1 (2.3) years] with renal transplants treated for 1 year with recombinant human growth hormone (rhGH), 30 U/m² per week. Height velocity [mean (SD), cm/year increased from 4.7 (1.3) to 9.7 (2.1) (P<0.0001) in the CRF group and 3.1 (1.6) to 7.3 (2.8) (P<0.0001) in the transplant group. In the CRF group, there was a correlation between age and height velocity, both in the pretreatment year (r=–0.755,P<0.0001) and during treatment (r=–0.421,P=0.045). There was no correlation between pretreatment height velocity or GFR and response to rhGH. In the transplanted children height velocity during the treatment year correlated with age (r=–0.647,P=0.007), prednisolone dose (r=–0.689,P=0.003), GFR (r=0.542,P=0.030) and pretreatment height velocity (r=0.655,P=0.006). Multiple regression analysis showed prednisolone dose and age to be the most important predictors of response.     

“Low-dose” growth hormone therapy during peritoneal dialysis or following renal transplantation

The minimal effective dose of growth hormone (GH) to promote growth in children on dialysis or following renal transplantation remains unsettled. In order to study the issue, low-dose GH was administered to children with end-stage renal disease (ESRD) receiving chronic automated peritoneal dialysis (APD,n = 6, 4 males, 2 females) or following renal transplantation (T,n = 9, 8 males, 1 female). No APD patient was GH deficient, while 1 T patient (no. 2) had data consistent with GH deficiency, although he was obese (body mass index = 34 kg/m²). The mean dose of GH after 6 and 12 months of treatment was 0.16±0.02 and 0.22±0.07 versus 0.16±0.03 and 0.27±0.21 mg/kg per week for APD and T patients, respectively. When analyzing all patients, there were no significant differences before or after 6 and 12 months of GH therapy within or between the two groups, in terms of height velocity, bone age, renal function (in the T group) and height Z-scores (Z-Ht). However, the height velocity Z-score (Z-HV) increased significantly at 6 and 12 months compared with baseline in the APD patients only (P < 0.05). When the 2 T patients with the most impaired renal function were excluded from the analysis, Z-HV also increased significantly in the T patients after 12 months of GH (P < 0.02). We conclude that following low-dose GH therapy, children with ESRD treated with APD or T have similar increases in HV, allowing maintenance of Z-Ht but not catch-up growth.Presented, in part, at the 75th Annual Meeting of The Endocrine Society, 10 June 1993, Las Vegas, Nevada, USA     

Growth in children with chronic renal failure and after renal transplantation

Growth retardation is a major problem for many children with chronic renal failure (CRF) and transplantation. The aim of this study is to assess the relation between height, glomerular filtration rate (GFR), hormonal alterations in children with CRF on regular haemodialysis (HD), and the impact of functioning graft after kidney transplantation. Thirty-six hemodialysed children were included in the study beside 32 pediatric transplants. Mean duration on HD was 14.72 ± 7.73 months for the CRF group, while the mean interval after transplantation was 1.97 ± 0.9 years for the second group. Moreover, twenty healthy children of matched age and sex served as controls. Assessment of growth parameters included height, expressed as standard deviation scores (Ht SDS) for chronological age, serum levels of growth hormone (hGH), and parathormone (PTH). Growth performance was evaluated twice: at the start of the study and one year later. Children with CRF and transplantation had significantly higher levels of both serum hGH and PTH compared to their controls, while CRF children experienced significantly higher serum levels of both hGH and PTH compared to those with functioning graft. Furthermore, analysis of our results by non-parametric Kendall’s correlation at the start and one year later revealed negative correlation concerning dialysis duration, serum creatinine, and PTH. On the other hand, positive correlation was achieved for serum calcium and GFR.     

Long-term effects of growth hormone treatment on growth and puberty in patients with chronic renal insufficiency

Several prospective trials have shown that recombinant human growth hormone (GH) accelerates growth significantly during the first years of therapy, but the effects of long-term GH therapy with regard to long-term growth response and safety have not yet been established. Forty-five Dutch prepubertal children [28 boys, 17 girls, mean (SD) age 7.8 (3.4) years] with chronic renal insufficiency (CRI) and severe growth retardation started GH therapy between 1988 and 1991 within one of the randomized Dutch trials. Long-term GH therapy, in this study a maximum of 8 years, resulted in a sustained and significant improvement of height standard deviation score (SDS) compared with baseline values (P<0.001). The mean height SDS reached the lower end (-2 SDS) of the normal growth chart after 3 years of GH therapy. During the following years the mean height SDS gradually increased, thereby approaching the mean target height SDS after 6 years of GH therapy. Three factors were significantly associated with the height SDS after 4 years of GH therapy: height SDS at the start (+) of therapy, age at the start of therapy (-), and the duration of dialysis treatment (-). Bone maturation did not accelerate during long-term GH therapy. Children on a conservative regimen at the start of GH therapy had no accelerated deterioration of renal function during 6 years of GH therapy. The average daily GH dose administered over the years had no significant influence on the glomerular filtration rate after 4 years. GH therapy had no adverse effects or significant effect on parathyroid hormone concentration, nor were there any radiological signs of renal osteodystrophy. Puberty started at a median age, within the normal range, of 12.4 years in boys and 12.0 years in girls, respectively. Long-term GH therapy leads to a sustained improvement in height SDS in children with growth retardation secondary to CRI, resulting in a normalization of height in accordance with their target height SDS, without evidence of deleterious effects on renal function or bone maturation. A GH dosage of 4 IU/m² per day appears efficient and safe. Our long-term data show that final height will be within the normal target height range when GH therapy is continued for many years. Received: 25 March 1999 / Revised: 13 January 2000 / Accepted: 20 January 2000     

Growth after conversion to alternate-day corticosteroids in children with renal transplants: a single-center study

During the 1980s all children with growth potential and stable/adequate renal function at 6–9 months after kidney transplantation underwent conversion to alternate-day corticosteroids in an attempt to maximize growth. Conversion was attempted in 79 of 160 children who received allografts during this decade and was considered successful if they remained on alternate-day prednisone for more than 1 year, with a calculated creatinine clearance of at least 75% of the pre-conversion baseline value. Conversion succeeded in 55 children but failed in 24. Growth was markedly improved among those successfully converted when compared with the failure group, as measured by standard deviation score for growth velocity based on chronological age (+0.94±1.58 vs. –0.86±1.53,P<0.001) and bone age (+0.49±0.61 vs. –1.24±1.47,P<0.001). The improved growth among the successfully converted patients is believed to have been related to the combined effects of lower corticosteroid dose (0.36±0.16 vs. 0.48±0.21 mg/kg per day,P<0.02) and better renal function (calculated creatinine clearance 87±32 vs. 47±21 ml/min per 1.73 m²,P<0.001) at 1 year post conversion. Two factors appeared to improve the likelihood of successful conversion: the use of cyclosporine and receiving a live-related rather than cadaver transplant. Cyclosporine was associated with improvement in the overall rate for successful conversion in all recipients, from 59% to 83% (P<0.05). Recipients of allografts from live-related donors underwent successful conversion in 90% of cases compared with 58% receiving cadaver allografts (P<0.05). Successful conversion to alternate-day corticosteroid therapy is of significant benefit for linear growth, but may be associated with a risk of rejection and loss of renal function. The risk is small in live-related recipients and has been made safer for cadaver recipients with the introduction of cyclosporine.     

Growth in young children with chronic renal failure

Statural growth and its relation to growth potential, renal function, blood urea nitrogen (BUN), mineral metabolism hormones and dietary intake were studied in 17 prepubertal children (aged 1.6–9.3 years) on conservative treatment for chronic renal failure due to tubulo-interstitial nephropathy. Statural growth (height SDS) was related to the degree of renal failure, was more retarded than ossification, and was independent of the chronological age of the patients. We observed that the lower the glomerular filtration rate (GRF), the lower was the growth potential (increased bone age/statural age ratio). Growth velocity may be normal regardless of statural and bone maturation delay and the degree of renal insufficiency. Impaired growth rate correlated with parathyroid hormone levels, caloric intake and increased blood urea nitrogen during the year of observation. These data show that comprehensive monitoring and suitable treatment must be performed in order to prevent growth retardation at any GFR level.