Case Report Am J Nephrol 1992;12:471-473
Alberto Ortiza María Plácida Garróna Adela Rovirab Manuel Moliza Malte Banderasa Maribel Crespoa Jerónimo Sandiumengec Lw¿$ Hernandoa Carlos Carameloa
Effect of Recombinant Human Growth Hormone in a Postpediatric Hemodialysis Patient with Delayed Growth
Servicios de Nefrología, Endocrinología, y Pediatría, Fundación Jiménez Díaz, Madrid, España
Key Words
Abstract
Chronic renal failure Growth Recombinant human growth hormone
We present an 18-year-old patient who has been on renal replacement therapy since the age of 11. He had growth retardation and delayed puberty, with a bone age of 13.6 years. Treatment with human recombinant growth hormone (rhGH) resulted in a clearcut increase in height and lean body mass. We emphasize that rhGH treatment could be tried even at a postpediatric age. provided bone radiology suggests that further growth is possible.
Introduction
Case Report
Received: November 8. 1991 Accepted: September 22. 1992
An 18-year-old male who had been on renal replacement therapy for 7 years was evaluated for growth retardation and delayed puber ty. Panarteritis nodosa had been diagnosed in 1980. and long-term treatment with prednisone applied. In February' 1983 he was referred to hemodialysis. In June 1984 he received a kidney graft from his father. Immunosuppression included azathioprine and prednisone. In 1985 bone radiology revealed osteoporosis and a vertebral frac ture. As a consequence of chronic rejection, hemodialysis was reini tiated in November 1986. and the graft was excised in January 1987. In March 1989 a second cadaveric graft was implanted and he received azathioprine, prednisone and cyclosporine. In September 1989, a diagnosis of graft rejection was made and in October 1989, he was back to hemodialysis. The next month the graft was removed, and recombinant human erythropoietin (rHuEPO) was begun. In February 1990. he was transferred to our Adult Dialysis Unit, where he has been dialyzed according to a similar schedule and maintaining a similar Kt/V as in the Pediatric Unit. At the time his weight and height were respectively 30.5 kg and 144 cm; no significant height or weight changes had been recorded in the previous 2 years. Bone age, determined by TW2 standards, was 13.8 years [9] and the expected
C. Caramelo Laboraiorio de Nefrología Fundación Jiménez Díaz Av. Reyes Católicos 2 28040 Madrid (Spain)
© 1992 S. Karger AG, Basel 0250-8095/92/0126-0471 $2.75/0
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 6:00:09 AM
Growth retardation and delayed puberty are common disturbances in uremic children, and uremic growth fail ure is not improved by regular dialysis [1]. Unlike other types of growth retardation, the serum concentration of growth hormone in uremia is frequently high [2]. More over, serum immunoreactive insulin-like growth factor-1 (IGF-1) level is within the normal range, although IGF-1 bioactivity is decreased, perhaps due to increased levels of circulating IGF-binding proteins [2], Recently, the paren teral administration of recombinant human growth hor mone (rhGH) has been reported to promote growth in uremic and transplanted prepubertal children [3-8], We report the favorable growth response to rhGH of a patient transferred to our Adult Dialysis Unit from a pediatric unit, in whom, in spite of his chronological age, bone radi ology indicated that further growth was possible.
Table 1. Measurements prior to and during the first 12 months on rhGH therapy
Age years
Height m
Mean bone age, years
SDS
GV cm/year
18.2 18.5 19.2 19.5
1.440 1.445 1.505 1.525
13.8
-2.07
1.5 (annualized)
14.3
-1.89
GV (bone age) centiles
8
460 pmol/1. radioimmunoassay, Sorine Biomedica, Sauggia, Italy). When he was 18.5 years old, rhGH (Genotonorm R, Kabi Fides, Spain) was begun at a dose of 4 IU/days s.c., 6 days a week. Tables 1 and 2 show the anthropometric data, which demonstrate a rapidappearance, sustained growth stimulation. Growth velocity in creased from 1.5 (annualized) to 8 cm/year. and standard deviation score (SDS) related to bone age improved from 2.07 to 1.89 (II], Seven months later, the bone age was 14.3 years. Weight gain corre sponded to lean body mass, as no increase was evident in adipose tissue parameters. The patient has also noticed an increase in libido in the last 3 months. Simultaneously with the change in libido, a pro gress of secondary sexual characteristics was observed, with a change of pubic hair from stage 2 (Tanner P2) to stage 3 (Tanner P3) [12].
472
Arm circum ference, cm
Testicular volume, ml
Pubic hair stage
4
P2
7
p3
20 20
22.7 2 2 .8
There were no clinical or biochemical side effects of rhGH and the dialysis prescription was not changed. HbAlc levels have remained within normal limits.
Discussion
The presented patient had been on renal replacement therapy since childhood, and at the time he was trans ferred to our hospital exhibited a multifactorial growth retardation related to chronic renal failure, graft rejection, corticosteroid treatment and malnutrition. Although he was 18 years old, puberty was delayed and bone radiology suggested that growth was still possible. On this basis, a trial of rhGH therapy was deemed adequate. The results of rhGH administration were positive in two aspects, increased growth velocity and increased muscular mass and weight. Although the contribution of other factors such as rHuEPO administration or catch-up growth after corticosteroid withdrawal remain to be defined, the strik ing temporal association between rhGH therapy and growth response strongly suggests that rhGH was respon sible for this phenomenon. There are several recent reports suggesting that rhGH treatment of uremic prepu bertal children can promote growth even in the presence of normal or increased serum GH [3-8], No influence of
Ortiz/Garrón/Rovira/Moliz/Banderas/ Crespo/Sandiumenge/Hemando/Caramelo
Growth Hormone in Hemodialysis
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 6:00:09 AM
Table 2. Auxiological and pubertal development parameters
concomitant rHuEPO administration on the response to rhGH has been described [7], Results are less easy to interpret in pubertal patients because of the possible con founding effect of the pubertal growth spurt and the lack of parameters from uremic children. Preliminary data in pubertal renal transplant recipients are inconclusive [8], although the response of dialysis patients to rhGH may differ. A beneficial anabolic effect has been found in ure mic children on rhGH therapy [2], as well as in malnour ished adult dialysis patients [13] and healthy elderly indi viduals [14]. Although we cannot exclude a role for the pubertal growth spurt in the growth réponse observed in this patient, there are several points suggesting that the contri bution of puberty was minor. First, testicular volume was only 4-5 ml 5 months after the beginning of rhGH thera py, and the peak height velocity is very rarely reached before the genitalia are in stage 4 [12], Second, in uremic children in dialysis pubertal growth is delayed, the inten sity of pubertal growth spurt is reduced (peak velocity being 2.7 cm/year) [ 1] and height SDS related to bone age usually declines during puberty [1, 15]. However, this patient’s height SDS improved, and peak growth velocity reached the 25th centile of healthy children when calcu lated for bone age. Finally, impaired secretion of GH is
usually associated with delayed onset of puberty and investigators have observed a relationship between exoge nous administration of GH and puberty and increased libido in nonuremic individuals [16]. Therefore, it is pos sible in this case that the administration of rhGH could have been involved, in association with other factors, in triggering puberty, instead of puberty triggering growth. This report therefore shows the outcome of the unusual situation of rhGH administration to induce growth in a postpediatric patient. The results suggest that a growthpromoting effect of rhGH may be expected at an age when administration of rhGH is usually not considered. There is one related communication [6] from the group of the University of California at Los Angeles, reporting no effect of rhGH in a 17.8-year-old CAPD patient; however, no individualized data were provided on the bone maturational stage of the patient which are undoubtedly rele vant to the success of rhGH treatment. While assessing the effect of rhGH in a particular uremic child during puberty is problematic, the main purpose of our paper is to remind physicians caring for young adult dialysis patients that chronological age should not deter them from considering the administration of rhGH to young adult patients, provided that bone age indicates that fur ther growth is possible.
References 6 Fine RN. Koch VH. Boechat ML et al: Recom binant human growth hormone (rhGH) treat ment of children undergoing peritoneal dialy sis. Peril Dial Int 1990;10:209-214. 7 Fine RN: Recombinant human growth hor mone treatment of children with chronic renal failure: update 1990. Acta Paediatr Scand 1990;370:44-48. 8 Johansson G, Sietnieks H, Janssens F, et al: Recombinant human growth hormone in short children with chronic renal disease, before transplantation or with functioning renal trans plant: An interim report on four European studies. Acta Paediatr Scand 1990:370:36-42. 9 Tanner JM, Whitehouse RH, Cameron N, Marshall WA. Healy MJR, Goldstein H: As sessment o f skeletal maturity and prediction of adult height (TW2 method), ed 2. London, Academic Press, 1983. 10 Bayley N, Pinneau SR: Tables for predicting adult height from skeletal age. Revised for use with the Greulich-Pyle hand standards. J Pe diatr 1952;40:426-441.
11 Tanner JM, Whitehouse RH, Takaishi M: Standards from birth to maturity for height velocity and weight velocity: British children. Arch Dis Child 1965;41:613-635. 12 Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13-23. 13 Kopple JD, Leiserowitz M. Brunori G, Mattimore C: Treatment of malnourished mainte nance hemodialysis patients with recombinant human growth hormone. J Am Soc Nephrol 1990:1:364. 14 Rudman D, Feller AG, Nagraj HS, ct al: Effects of human growth hormone in men over 60 years old. N Engl J Med 1990:323:1-6. 15 Schàrer K: Growth and development of chil dren with chronic renal failure. Acta Paediatr Scand 1990;366:90-92. 16 Sheikholislam BM, Stempfcl RS: Hereditay isolated somatotropin deficiency: Effects of hu man growth hormone administration. Pediat rics 1972:49:362-374.
473
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 6:00:09 AM
1 Kleinknecht C. Broyer M, Gagnadoux MF. et al: Growth in children with long-term dialysis. A study of 76 patients. Adv Nephrol 1980;9: 133-163. 2 Fine RN: Growth hormone and the kidney: The use of recombinant human growth hor mone (rhGH) in growth retarded children with chronic renal insufficiency. J Am Soc Nephrol 1991;1:1136-1145. 3 Koch VH, Lippe BM, Nelson PA, Boechat MI. Sherman BM, Fine RN: Accelerated growth after recombinant growth hormone treatment of children with chronic renal failure. J Pediatr 1989;115:366-371. 4 Tönshoff B. Mehls O. Heinrich U, Blum WF. Ranke MB. Schauer A: Growth-stimulating ef fects of recombinant human growth hormone in children with end-stage renal disease. J Pe diatr 1990;116:561-566. 5 Hokken-Koelega ACS, Stignen T. de Muinck Kezer-Schramer SMPF, et al: Placebo-con trolled, double-blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet 1991:338: 585-590.
Alberto Ortiza María Plácida Garróna Adela Rovirab Manuel Moliza Malte Banderasa Maribel Crespoa Jerónimo Sandiumengec Lw¿$ Hernandoa Carlos Carameloa
Effect of Recombinant Human Growth Hormone in a Postpediatric Hemodialysis Patient with Delayed Growth
Servicios de Nefrología, Endocrinología, y Pediatría, Fundación Jiménez Díaz, Madrid, España
Key Words
Abstract
Chronic renal failure Growth Recombinant human growth hormone
We present an 18-year-old patient who has been on renal replacement therapy since the age of 11. He had growth retardation and delayed puberty, with a bone age of 13.6 years. Treatment with human recombinant growth hormone (rhGH) resulted in a clearcut increase in height and lean body mass. We emphasize that rhGH treatment could be tried even at a postpediatric age. provided bone radiology suggests that further growth is possible.
Introduction
Case Report
Received: November 8. 1991 Accepted: September 22. 1992
An 18-year-old male who had been on renal replacement therapy for 7 years was evaluated for growth retardation and delayed puber ty. Panarteritis nodosa had been diagnosed in 1980. and long-term treatment with prednisone applied. In February' 1983 he was referred to hemodialysis. In June 1984 he received a kidney graft from his father. Immunosuppression included azathioprine and prednisone. In 1985 bone radiology revealed osteoporosis and a vertebral frac ture. As a consequence of chronic rejection, hemodialysis was reini tiated in November 1986. and the graft was excised in January 1987. In March 1989 a second cadaveric graft was implanted and he received azathioprine, prednisone and cyclosporine. In September 1989, a diagnosis of graft rejection was made and in October 1989, he was back to hemodialysis. The next month the graft was removed, and recombinant human erythropoietin (rHuEPO) was begun. In February 1990. he was transferred to our Adult Dialysis Unit, where he has been dialyzed according to a similar schedule and maintaining a similar Kt/V as in the Pediatric Unit. At the time his weight and height were respectively 30.5 kg and 144 cm; no significant height or weight changes had been recorded in the previous 2 years. Bone age, determined by TW2 standards, was 13.8 years [9] and the expected
C. Caramelo Laboraiorio de Nefrología Fundación Jiménez Díaz Av. Reyes Católicos 2 28040 Madrid (Spain)
© 1992 S. Karger AG, Basel 0250-8095/92/0126-0471 $2.75/0
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 6:00:09 AM
Growth retardation and delayed puberty are common disturbances in uremic children, and uremic growth fail ure is not improved by regular dialysis [1]. Unlike other types of growth retardation, the serum concentration of growth hormone in uremia is frequently high [2]. More over, serum immunoreactive insulin-like growth factor-1 (IGF-1) level is within the normal range, although IGF-1 bioactivity is decreased, perhaps due to increased levels of circulating IGF-binding proteins [2], Recently, the paren teral administration of recombinant human growth hor mone (rhGH) has been reported to promote growth in uremic and transplanted prepubertal children [3-8], We report the favorable growth response to rhGH of a patient transferred to our Adult Dialysis Unit from a pediatric unit, in whom, in spite of his chronological age, bone radi ology indicated that further growth was possible.
Table 1. Measurements prior to and during the first 12 months on rhGH therapy
Age years
Height m
Mean bone age, years
SDS
GV cm/year
18.2 18.5 19.2 19.5
1.440 1.445 1.505 1.525
13.8
-2.07
1.5 (annualized)
14.3
-1.89
GV (bone age) centiles
8
460 pmol/1. radioimmunoassay, Sorine Biomedica, Sauggia, Italy). When he was 18.5 years old, rhGH (Genotonorm R, Kabi Fides, Spain) was begun at a dose of 4 IU/days s.c., 6 days a week. Tables 1 and 2 show the anthropometric data, which demonstrate a rapidappearance, sustained growth stimulation. Growth velocity in creased from 1.5 (annualized) to 8 cm/year. and standard deviation score (SDS) related to bone age improved from 2.07 to 1.89 (II], Seven months later, the bone age was 14.3 years. Weight gain corre sponded to lean body mass, as no increase was evident in adipose tissue parameters. The patient has also noticed an increase in libido in the last 3 months. Simultaneously with the change in libido, a pro gress of secondary sexual characteristics was observed, with a change of pubic hair from stage 2 (Tanner P2) to stage 3 (Tanner P3) [12].
472
Arm circum ference, cm
Testicular volume, ml
Pubic hair stage
4
P2
7
p3
20 20
22.7 2 2 .8
There were no clinical or biochemical side effects of rhGH and the dialysis prescription was not changed. HbAlc levels have remained within normal limits.
Discussion
The presented patient had been on renal replacement therapy since childhood, and at the time he was trans ferred to our hospital exhibited a multifactorial growth retardation related to chronic renal failure, graft rejection, corticosteroid treatment and malnutrition. Although he was 18 years old, puberty was delayed and bone radiology suggested that growth was still possible. On this basis, a trial of rhGH therapy was deemed adequate. The results of rhGH administration were positive in two aspects, increased growth velocity and increased muscular mass and weight. Although the contribution of other factors such as rHuEPO administration or catch-up growth after corticosteroid withdrawal remain to be defined, the strik ing temporal association between rhGH therapy and growth response strongly suggests that rhGH was respon sible for this phenomenon. There are several recent reports suggesting that rhGH treatment of uremic prepu bertal children can promote growth even in the presence of normal or increased serum GH [3-8], No influence of
Ortiz/Garrón/Rovira/Moliz/Banderas/ Crespo/Sandiumenge/Hemando/Caramelo
Growth Hormone in Hemodialysis
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 6:00:09 AM
Table 2. Auxiological and pubertal development parameters
concomitant rHuEPO administration on the response to rhGH has been described [7], Results are less easy to interpret in pubertal patients because of the possible con founding effect of the pubertal growth spurt and the lack of parameters from uremic children. Preliminary data in pubertal renal transplant recipients are inconclusive [8], although the response of dialysis patients to rhGH may differ. A beneficial anabolic effect has been found in ure mic children on rhGH therapy [2], as well as in malnour ished adult dialysis patients [13] and healthy elderly indi viduals [14]. Although we cannot exclude a role for the pubertal growth spurt in the growth réponse observed in this patient, there are several points suggesting that the contri bution of puberty was minor. First, testicular volume was only 4-5 ml 5 months after the beginning of rhGH thera py, and the peak height velocity is very rarely reached before the genitalia are in stage 4 [12], Second, in uremic children in dialysis pubertal growth is delayed, the inten sity of pubertal growth spurt is reduced (peak velocity being 2.7 cm/year) [ 1] and height SDS related to bone age usually declines during puberty [1, 15]. However, this patient’s height SDS improved, and peak growth velocity reached the 25th centile of healthy children when calcu lated for bone age. Finally, impaired secretion of GH is
usually associated with delayed onset of puberty and investigators have observed a relationship between exoge nous administration of GH and puberty and increased libido in nonuremic individuals [16]. Therefore, it is pos sible in this case that the administration of rhGH could have been involved, in association with other factors, in triggering puberty, instead of puberty triggering growth. This report therefore shows the outcome of the unusual situation of rhGH administration to induce growth in a postpediatric patient. The results suggest that a growthpromoting effect of rhGH may be expected at an age when administration of rhGH is usually not considered. There is one related communication [6] from the group of the University of California at Los Angeles, reporting no effect of rhGH in a 17.8-year-old CAPD patient; however, no individualized data were provided on the bone maturational stage of the patient which are undoubtedly rele vant to the success of rhGH treatment. While assessing the effect of rhGH in a particular uremic child during puberty is problematic, the main purpose of our paper is to remind physicians caring for young adult dialysis patients that chronological age should not deter them from considering the administration of rhGH to young adult patients, provided that bone age indicates that fur ther growth is possible.
References 6 Fine RN. Koch VH. Boechat ML et al: Recom binant human growth hormone (rhGH) treat ment of children undergoing peritoneal dialy sis. Peril Dial Int 1990;10:209-214. 7 Fine RN: Recombinant human growth hor mone treatment of children with chronic renal failure: update 1990. Acta Paediatr Scand 1990;370:44-48. 8 Johansson G, Sietnieks H, Janssens F, et al: Recombinant human growth hormone in short children with chronic renal disease, before transplantation or with functioning renal trans plant: An interim report on four European studies. Acta Paediatr Scand 1990:370:36-42. 9 Tanner JM, Whitehouse RH, Cameron N, Marshall WA. Healy MJR, Goldstein H: As sessment o f skeletal maturity and prediction of adult height (TW2 method), ed 2. London, Academic Press, 1983. 10 Bayley N, Pinneau SR: Tables for predicting adult height from skeletal age. Revised for use with the Greulich-Pyle hand standards. J Pe diatr 1952;40:426-441.
11 Tanner JM, Whitehouse RH, Takaishi M: Standards from birth to maturity for height velocity and weight velocity: British children. Arch Dis Child 1965;41:613-635. 12 Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970;45:13-23. 13 Kopple JD, Leiserowitz M. Brunori G, Mattimore C: Treatment of malnourished mainte nance hemodialysis patients with recombinant human growth hormone. J Am Soc Nephrol 1990:1:364. 14 Rudman D, Feller AG, Nagraj HS, ct al: Effects of human growth hormone in men over 60 years old. N Engl J Med 1990:323:1-6. 15 Schàrer K: Growth and development of chil dren with chronic renal failure. Acta Paediatr Scand 1990;366:90-92. 16 Sheikholislam BM, Stempfcl RS: Hereditay isolated somatotropin deficiency: Effects of hu man growth hormone administration. Pediat rics 1972:49:362-374.
473
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 6:00:09 AM
1 Kleinknecht C. Broyer M, Gagnadoux MF. et al: Growth in children with long-term dialysis. A study of 76 patients. Adv Nephrol 1980;9: 133-163. 2 Fine RN: Growth hormone and the kidney: The use of recombinant human growth hor mone (rhGH) in growth retarded children with chronic renal insufficiency. J Am Soc Nephrol 1991;1:1136-1145. 3 Koch VH, Lippe BM, Nelson PA, Boechat MI. Sherman BM, Fine RN: Accelerated growth after recombinant growth hormone treatment of children with chronic renal failure. J Pediatr 1989;115:366-371. 4 Tönshoff B. Mehls O. Heinrich U, Blum WF. Ranke MB. Schauer A: Growth-stimulating ef fects of recombinant human growth hormone in children with end-stage renal disease. J Pe diatr 1990;116:561-566. 5 Hokken-Koelega ACS, Stignen T. de Muinck Kezer-Schramer SMPF, et al: Placebo-con trolled, double-blind, cross-over trial of growth hormone treatment in prepubertal children with chronic renal failure. Lancet 1991:338: 585-590.
