Recombinant human growth hormone treatment of children with chronic renal failure: long-term (1- to 3-year) outcome. Richard N. Finel, Kim Pyke-Grimml, ...
Pediatric Nephrology
Pediatr Nephml (I991) 5:477-481 9 IPNA 1991
Growth Original article
Recombinant human growth hormone treatment of children with chronic renal failure: long-term (1- to 3-year) outcome Richard N. Finel, Kim Pyke-Grimml, Pauline A. Nelsonl, M. Ines Boechat 2, Barbara M. Lippe3, Ora Yadin 1, and Elaie Kamil Departments of 1 Pediatrics and 2 Radiology and the Divisions of i Pediatric Nephrology and 3pediatric Endocrinology, University of California at Los Angeles, Center for Health Sciences, Los Angeles, California, USA Received September 25, 1990
Abstract. Treatment o f nine boys, aged 2 . 8 - 1 6 . 3 years, with growth retardation consequent to chronic renal failure (CRF), with recombinant h u m a n growth hormone (rhGH) for 1 2 - 3 6 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 o f treatment. The mean calculated creatinine clearance did not decrease significantly during the 36 months o f treatment; however, two patients required institution of dialysis at 18 and 30 months following the initiation of r h G H treatment. There was no exacerbation o f the glucose intolerance o f uremia following r h G H treatment. Currently, six o f 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 -ZOO, and are above the 5th per centile for chronological age on the growth curve. These data indicate that r h G H treatment of growthretarded children with C R F results in accelerated growth velocity during the 2nd and 3rd years o f treatment, and demonstrate the potential for such children to achieve normal stature for chronological age despite the continued presence o f renal failure. Key words: Chronic renal failure - Growth retardation H u m a n growth h o r m o n e
Introduction The studies by Mehls and Ritz [1] reported in 1983 were the first to demonstrate that supraphysiological doses of
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heterologous (procine) growth h o r m o n e (GH) could improve the growth velocity o f growth-retarded uremic rats. Subsequent studies using recombinant human G H (rhGH) [2, 31 and rat G H [4] in the 7/8 [2, 3] and 3/4 [41 uremic rat model were confirmatory. In N o v e m b e r 1986 studies were initiated at our institution to determine the efficacy o f r h G H in increasing the growth velocity of growth-retarded children with chronic renal failure (CRF). Initial reports from our institution demonstrating the short-term (6- to 12-month) salutary effects o f such treatment have been published previously [ 5 - 7 ] . This report describes the long-terrn (12- to 36month) outcome o f r h G H treatment in nine growth-retarded [standard deviation score (SDS) o f height more negative than -2.00] children with CRF.
Patients and methods Patients. Nine males, aged 2.8-16.3 years, were entered into the study.
The entrance criteria were as follows: (1) CRF with a calculated creatmine clearance (Ccr) [8] between 5 and 75 ml/min per 1.73 m2; (2) growth retardation with a SDS of height more negative than -2.00; (3) bone age of less than 12.5 years for boys and less than 11.0 years for girls; (4) pubertal stage Tanner II or le~s; (5) no obvious clinical evidence for another unrelated etiology for the growth retardaton. The exit criteria were as fQllows:(1) attainment of the 50th percentile for mid-parental target height on the growth curve; (2) renal transplantation; (3) significant related side-effects. The age at initiation of rhGH treatment, primary renal disease, duration of rhGH treatment, SDS of height at initiation of rhGH treatment and current status of the nine patients enrolled into the protocol who have been followed for at least 1 year are shown in Table 1. Treatmentprotocol. The treatment protocol was approved by the University of California at Los Angeles Human Subjects Protection Committee and written informed consent was obtained from each parent and/or patient prior to initiation of the study. Caretakers and/or patients were trained to administer the rhGH subcutaneously. Genentech (South San Francisco, CA) provided the rhGH - Protropin methionyl hGH - in 5 mg vials, each of which was reconstituted with 1 ml of bacterostatic water. The initial dosage of rhGH in patients l - 8 was 0.125 mg/kg thrice weekly. This was switched to 0.053 mg/kg daily at 6-24 months follow-
478 T a b l e 1. Patient data
Patient Age Renal disease no. (years) 1. 2. 3. 4. 5. 6. 7. 8. 9.
6.6 4.9 4.1 2.9 2.8 8.1 5.8 16.3 9.4
PUV Dysplasia PUV Dysplasia Dysplasia Cystinosis Dysplasia Alagillesyndrome Dysplasia
Table 2. Recombinant human growth hormone (rhGH) treatment in CRF Duration of SDS treatment (months)
Current status
18 36 36 36 36 24 24 18 12
Post-transplant Post-transplant CRF CRF CRF CRF CRF CRF CRF
-3.67 -2.18 -2.16 -3.40 -3.38 -2.17 -2.40 -5.93 -3.34
PUV, posterior urethral valves; SDS, standard deviation score of height;
CRF, chronic renal failure
ing initiation of the study. The daily dose was doubled at 6 months in patient no. 9 because the annual growth velocity did not increase more than 50% of that achieved the previous year. Patient no. 9 had been treated intermittently with other GH preparations on a thrice weekly schedule since age 4 years but on entry to the study daily rhGH treatment was initiated. Endocrine studies. Blood was taken from patients 1 - 7 at 30-min intervals over a 24-h period for GH estimation prior to initiation of the rhGH treatment. In addition, patients 1 - 8 underwent an L-DOPA/propranolol GH stimulation test as described by Fass et al. [9]. The latter was performed prior to initiation of rhGH treatment in patients 6 - 8 and at the end of 1 year of rhGH treatment following discontinuation of treatment for 10 days in patients 1-5. GH determinations were performed at Genentech using a commercially available solid-phase two-site immunoradiometric assay (Hybdritech, LaJolla, Calif.) Plasma insulin-like growth factor (IGF-1) determinations were performed following acid chromatography [10] by Dr. Raymond Hintz of Stanford University School of Medicine (Palo Alto, Calif.) at baseline and at 6-month intervals thereafter. The anti-rhGH antibody assay was performed at Genentech at 6-month intervals following initiation of rhGH treatment. Each patient had a fasting and 2-h post-prandial blood glucose and insulin determination prior to initiating the study and at 6-month intervals thereafter. Patients 1 - 5 underwent an oral glucose tolerance test (OGTT) prior to initiating rhGH treatment and at 6 and 12 months following treatment as previously described [6]. Thyroid function studies [thyroxine (T4) and thyroid-stimulating hormone (TSH)] were performed prior to initiating the study and at 6-month intervals thereafter.
Patient no.
1. 2. 3. 4. 5. 6. 7. 8. 9. Mean _+ SD - 12 months
Growth velocity (cm/year) - 12 months
12 months
4.8 6.3 6.3 3.0 4.3 5.0 5.7 3.0 6.7 5.0 1.4 vs P =
8.7 10.7 7.5 8.6 9.2 7.2 8.9 6.2 a 9.5 a 8.5 1.3 0.0001
24 months
36 months
7.7 9.8 a 8.1 5.6 8.2 ~ 9.82
9.5 7.3 a 9.6 a 6.0 a
8.2 1.6
