Effects of recombinant human growth hormone on renal function in children with renal transplants

doi:10.1016/S0022-3476(96)70386-4

The Journal of Pediatrics

Volume 128, Issue 2, February 1996, Pages 177-183

https://doi.org/10.1016/S0022-3476(96)70386-4 Get rights and content

Abstract

OBJECTIVE: To provide accurate measurement of renal function during treatment with recombinant human growth hormone (rhGH). METHODS: We measured glomerular filtration rate and effective renal plasma flow by clearance of inulin and para-aminohippuric acid before rhGH therapy, after 1 week, and then at 6-month intervals for up to 2 years of treatment in 16 children (mean [SD] age = 13.1 [2.2] years; glomerular filtration rate = 52 [27] ml/min per 1.73 m²). The mean (SD) time from transplantation was 6.5 (3.6) years. RESULTS: Linear growth velocity during rhGH therapy increased from 4.0 (1.8) to 8.8 (2.6) cm/yr (p <0.0001). One child was withdrawn after 9 months because of abnormal glucose tolerance, and another child received a second renal transplant after 18 months. Glomerular filtration rate increased to 57 (29) ml/min per l.73 m² at 1 week (p = 0.004), remained improved at 6 months (63 [30]; p = 0.013), but was not significantly better at 1 year (59 [33]). Effective renal plasma flow on day 1 was 237 (127) ml/min per 1.73m² and was unchanged on day 8 (244 [123]), at 6 months (271 [149]), and after 1 year (269 [157]). During the study there was no significant change in filtration fraction, blood pressure, or kidney volume, and excretion of microalbumin and N-acetylglucosaminidase was unaltered. There was one rejection episode per 14.8 patient-months in the year before treatment, 1 per 18.9 patient-months during the first year of treatment, and 1 per 13 patient-months during the second year of rhGH therapy. CONCLUSION: Treatment with rhGH improves growth in children with renal transplants. Glomerular filtration rate was increased after 1 week and 6 months of rhGH therapy but returned to baseline values thereafter. The data indicate the need for long-term follow-up of children with renal transplants who are receiving rhGH. (J PEDIATR 1996;128:177-83)

Section snippets

METHODS

Sixteen children (four girls) from two pediatric nephrology centers in London were entered into the study, which lasted for 2 years and was part of a large international multicenter trial that is still in progress. More detailed renal function studies were performed in this subgroup of patients, who are therefore described separately. In the first year, children were randomly selected either to receive treatment or to have no treatment; in the second year, all children received rhGH. Results

RESULTS

Fifteen children completed 1 year, seven completed 18 months, and six have completed 2 years of rhGH treatment. Fasting hyperglycemia developed in patient 6, in association with a raised concentration of hemoglobin A_1c after 9 months, at which time rhGH treatment was stopped.

Two children (patients 7 and 11) had poor graft function at the start of the trial; both had biopsy-proven chronic rejection. Patient 11 received a second graft after 18 months of treatment with rhGH; patient 7 completed 2

DISCUSSION

We found that rhGH treatment in children with renal transplants resulted in an increase in GFR after 1 week and 6 months, with a return to pretreatment values by 1 year. There was no significant change in ERPF or in kidney volume. There are a number of mechanisms whereby rhGH could affect renal function. First, GH, through the action of IGF-I, increases GFR and ERPF in the normal kidney; micropuncture studies in the rat demonstrate that this is due to an effect on glomerular hemodynamics.²²

References (31)

R Hirschberg et al.
The delayed effect of growth hormone on renal function in humans
Kidney Int
(1989)
M Broyer et al.
Recombinant growth hormone in children after renal transplantation [Letter]
Lancet
(1994)
B Tonshoff et al.
Efficacy and safety of growth hormone treatment in short children with renal allografts: three-year experience
Kidney Int
(1993)
ACS Hokken-Koelega et al.
Growth hormone treatment in growth-retarded adolescents after renal transplantation
Lancet
(1994)
A Tejani et al.
Factors predictive of sustained growth in children after renal transplantation
J Pediatr
(1993)
SM Tucker et al.
Automated assay of N-acetyl-β-glucosaminidase in normal and pathological human urine
Clin Chim Acta
(1975)
G Tyden et al.
Acute renal graft rejection after treatment with human growth hormone
Lancet
(1990)
ID Schwartz et al.
Cadaveric renal allograft rejection after treatment with recombinant human growth hormone
J Pediatr
(1992)
D Ikkos et al.
Glomerular filtration rate and renal plasma flow in acromegaly
Acta Endocrinol
(1956)
M Bozzola et al.
GHRH and the immune system
Growth Factors
(1991)

L Rees et al.

Treatment of short stature in renal disease with recombinant human growth hormone

Arch Dis Child

(1990)

MR Benfield et al.

Treatment of growth failure in children after renal transplantation

Transplantation

(1993)

RN Fine et al.

Extended recombinant human growth hormone treatment after renal transplantation in children

J Am Soc Nephrol

(1992)

S Bartosh et al.

Effects of growth hormone administration in pediatric renal allograft recipients

Pediatr Nephrol

(1992)

G Johansson et al.

Recombinant human growth hormone treatment in short children with chronic renal disease, before transplantation or with functioning renal transplants: an interim report on five European studies

Acta Paediatr Scand

(1990)

Cited by (31)

Growth and Puberty in Chronic Kidney Disease
2008, Comprehensive Pediatric Nephrology: Text with CD-ROM
Growth and Puberty in Chronic Kidney Disease
2008, Comprehensive Pediatric Nephrology
Growth after organ transplantation
2006, Seminars in Pediatric Surgery
Growth is an important feature of childhood, but it is usually impaired before and after organ transplantation. Modest catch-up growth often occurs after renal transplantation. Nevertheless, patients remain short due to the effects of steroids used for immunosuppression. Children with chronic liver failure are also growth impaired, although not to the same extent. They also frequently have poor catch up growth after transplantation, again due to steroids. There are several randomized controlled clinical trials reporting growth hormone (GH) use after renal transplantation. These consistently show a beneficial effect of GH on linear growth. Patients with histories of frequent acute rejections before GH may have increased risk of acute rejection during treatment. Few data exist on liver transplant patients, although GH also appears effective. GH use may be safe and effective for renal transplant recipients who have been stable without acute rejection episodes. There needs to be long-term study of GH use in liver and renal transplant patients. It is critical to focus efforts on improving growth in renal failure before transplantation through GH use and to improve posttransplant growth in all recipients by minimizing steroid exposure.
Current status of kidney transplant: Update 2003
2003, Pediatric Clinics of North America
Recombinant human growth hormone post-renal transplantation in children: A randomized controlled study of the NAPRTCS
2002, Kidney International
Citation Excerpt :
The efficacy of rhGH in improving the growth velocity in renal allograft recipients had been demonstrated in multiple open label studies10-25 over the past decade when comparing growth velocity during the year prior to rhGH treatment to either one, two or three years of rhGH treatment. This has been shown in both prepubertal and pubertal recipients21,23. In pubertal recipients, initiation of rhGH treatment during the latter stages of puberty also has been shown to be efficacious21.
Recombinant human growth hormone post-renal transplantation in children: A randomized controlled study of the NAPRTCS.
Growth retardation persists in renal allograft recipients despite successful transplantation. The etiology is multi-factorial including the adverse effects of corticosteroids, suboptimal allograft function, and perturbations of the GH/GF axis. Recombinant human growth hormone (rhGH) has been effective in improving growth velocity; however, allograft dysfunction has been reported. Therefore, a randomized controlled study was undertaken.
Sixty-eight growth retarded pediatric renal allograft recipients were enrolled in a one-year randomized controlled study to determine the efficacy and safety of rhGH. A protocol biopsy was performed prior to enrollment.
After one year, the delta SDS (standardized height) was +0.49 ± 0.10 in the treatment group (N = 30) compared to -0.10 ± 0.08 in the control group (N = 22; P < 0.001). During the first year, there were no rejection episodes in the treatment group and three in the control group. After the first year, when all recipients were receiving rhGH, there were three patients in the treatment group and two patients in the control group who experienced an acute rejection episode. Prior to enrollment, more than one acute rejection episode was predictive of a subsequent rejection following enrollment. There was no difference in adverse events between the two groups.
In conclusion, rhGH is effective in improving the growth velocity of pediatric renal allograft recipients and is not associated with an increase in adverse events.
The impact of recombinant human growth hormone treatment during chronic renal insufficiency on renal transplant recipients
2000, Journal of Pediatrics
Citation Excerpt :
An analysis of the data from the published reports10 indicated that indeed ARE or progression of chronic rejection was noted in recipients receiving rhGH. However, in those reports attempting to compare the incidence of ARE before and after rhGH treatment or to compare the incidence retrospectively with a concurrent control group of recipients not receiving rhGH, no increase in the incidence of an adverse effect on graft function with rhGH treatment was noted.11-13 A prospective controlled study of 96 recipients failed to demonstrate a significant increase in the incidence of ARE after 1 year of rhGH when compared with a control group of recipients not receiving rhGH.14
Objective: To evaluate post-transplant outcomes for patients treated with human growth hormone (rhGH) during the course of chronic renal insufficiency (CRI). Study design: Patients (the “cohort” group) were identified who had been enrolled in 2 controlled studies to determine the efficacy and safety of rhGH in growth-retarded children with CRI and were subsequently enrolled in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) and received a renal transplant. Patient survival, graft survival, time to first acute rejection episode, causes of graft failure, adverse events, and serial growth data from transplant to 60 months were evaluated. Data from the cohort group of 102 patients were compared with data from 4913 primary transplants from “other NAPRTCS” recipients (the “control” group). Results: No significant difference was seen in patient survival or graft survival, incidence of acute rejection episode, or time to first rejection episode between the cohort and control groups. No specific adverse events were attributable to previous rhGH treatment. Only 2 patients had post-transplant lymphoproliferative disease in the cohort group, with no other malignancies reported. The mean height z scores in the cohort group at baseline and 60 months after transplant were –1.92 and –1.90, and the Δz score at 60 months was +0.20 compared with the control group (–1.88 and –2.10). Conclusions: Treatment of growth-retarded patients with CRI does not adversely affect graft function after renal transplantation. “Catch-down” growth does not occur after renal transplantation. (J Pediatr 2000;136:376-82)

View all citing articles on Scopus

^☆: From the Department of Paediatric Nephrology and Renal Research Unit, Royal Free Hospital, Pond Street, Hampstead, London, and the Children's Renal Unit, Evelina Children's Hospital, and the Department of Radiology, Guy's Hospital, London, United Kingdom

^☆☆: Supported by a grant from Action Research; the growth hormone was provided by Pharmacia Ltd.

^★: Reprint requests: H. Maxwell, MBChB, MRCP, Division of Nephrology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada.

^★★: 0022-3476/96/$5.00 + 0 9/20/69219

View full text

Effects of recombinant human growth hormone on renal function in children with renal transplants☆,☆☆,★,★★

Abstract

Section snippets

METHODS

RESULTS

DISCUSSION

Kidney Int

Lancet

Kidney Int

Lancet

J Pediatr

Clin Chim Acta

Lancet

J Pediatr

Glomerular filtration rate and renal plasma flow in acromegaly

Acta Endocrinol

GHRH and the immune system

Growth Factors

Treatment of short stature in renal disease with recombinant human growth hormone

Arch Dis Child

Treatment of growth failure in children after renal transplantation

Transplantation

Extended recombinant human growth hormone treatment after renal transplantation in children

J Am Soc Nephrol

Effects of growth hormone administration in pediatric renal allograft recipients

Pediatr Nephrol

Recombinant human growth hormone treatment in short children with chronic renal disease, before transplantation or with functioning renal transplants: an interim report on five European studies

Acta Paediatr Scand