Acta Padiatr Scand [Suppl] 366: 90-92,
1990
SHORT COMMUNICATION
Growth and Development of Children with Chronic Renal Failure K. SCHARER on behalf of the STUDY GROUP ON PUBERTAL DEVELOPMENT IN CHRONIC RENAL FAILURE From the Department of Paediatric Nephrology. Universiry of Heidelberg. Heidelberg, West Germany
ABSTRACT. Schiirer, K. on behalf of the Study Group on Pubertal Development in Chronic Renal Failure. (Department of Paediatric Nephrology, University of Heidelberg, Heidelberg, West Germany). Growth and development of children with chronic renal failure. Acta Paediatr Scand [Suppl] 366: 90, 1990. Preliminary results from an ongoing multicentre study on pubertal growth and sexual maturation in chronic renal failure are presented. Puberty was delayed by approximately 2.5 years in both sexes in children with chronic renal failure. There was also M irreversible decline in height SDS during puberty. The pulsatile secretion of growth hormone (GH) and luteinizing hormone (LH)were disrupted in patients on conservative treatment or dialysis compared with those in patients with renal transplants; the mean nocturnal GH level and the mean GH peak amplitude were increased, while the number of pulses and peak amplitude of LH were decreased. The biopotency of LH, expressed as the ratio of bioactive to immunoreactive LH, was suppressed in patients with renal transplants. Key words: Chronic renal failure, dehyed pubem, growth failure, gmwth hormone secretion, gonadotrophin secretion.
Growth failure is one of the unsolved problems in children with chronic renal insufficiency (1). The scope of the problem was first recognized some 20 years ago, soon after renal transplantation became available as a therapeutic option. A number of studies have shown that the growth failure is not improved by regular dialysis (2, 3). On the contrary, growth retardation tends to progress during dialysis therapy, resulting in a loss of relative height as determined by height SDS. The growth failure becomes even more pronounced during puberty. In comparison with the results of the First Zurich Longitudinal Growth Study, the onset of the pubertal growth spurt is delayed by approximately 2.5 years in children with chronic renal failure, and the intensity of the growth spurt is also significantly reduced (unpublished results). Malnutrition has been postulated as the main factor responsible for the growth retardation, and a number of studies have shown that nutritional supplementation will stimulate growth in children with chronic renal failure (4). However, other causative factors have been indicated, including metabolic acidosis, hyposthenuria, mineral depletion, uraemic bone disease associated with changes in vitamin D metabolism, and deficiencies of insulin-like growth factors, thyroid hormones and gonadal steroids. It is not yet known whether uraemic toxins are involved in the growth failure, or to what extent renal transplantation itself interferes with normal growth. A multicentre study involving eight paediatric nephrology centres was started 2 years ago and is still currently in progress. The aims of this study are to analyse growth and sexual maturation in pubertal patients in various stages of chronic renal failure, and to determine whether chronic renal failure causes changes in the secretion of hormones regulating the hypothalamo-pituitary-gonadal axis. In particular, the physiological pulsatile secretion of growth hormone (GH) has been investigated in order to assess whether a characteristic pattern of GH secretion is associated with chronic renal failure. This report presents preliminary results from the study.
Acta Paediatr &and [Suppl] 366
Growth in chronic renal failure
PATIENTS AND METHODS Patients with chronic renal failure were selected to enter the study if they were older than 10 years, in pubertal stage I or I1 according to Tanner's staging and, in boys, if the testicular volume was less than 4 ml. In children on conservative treatment (n = 32). creatinine clearance had to be less than 25 mllminutell.73 m2. Patients were also included in the study during treatment by haemodialysis or peritoneal dialysis (n = 9). or after transplantation (n = 22). Children receiving erythropoietin or GH treatment or with systematic disorders such as cystinosis, oxalosis and severe malformation syndromes were excluded. Each patient underwent a clinical examination and laboratory tests every 6 months, and an investigation of hormone secretion every I2 months. For determination of GH and luteinizing hormone (LH) levels, blood samples were withdrawn every 15 minutes from 20.00 hours to 07.00 hours. Other plasma hormones. including follicle stimulating hormone (FSH). prolactin, testosterone, dihydrotestosterone (in boys), oestradiol (in girls), adrenal androgens, insulin-like growth factor I and melatonin, were measured at less frequent intervals. Most hormones were measured by radioimmunoassay; bioactive LH was measured using a mouse Leydig cell assay. Sleep was recorded visually, and hormone profiles were analysed using the Cluster and Pulsar peak detection methods.
RESULTS In the 2-year period up to August 1989, 46 boys and 17 girls were entered into the study. These children had a mean chronological age of 12.8 f 2.0 years (f SD) and a mean bone age delay of 2.5 years (mean bone age 10.3 f 1.9 years). Preliminary results from this group of children showed a decline in height SDS during puberty, height SDS being related to bone maturation. Two patterns of spontaneous GH secretion were observed (unpublished results). During dialysis treatment there was a high baseline level of GH with high amplitude peaks, while after renal transplantation the baseline GH level and peak amplitude were much lower. During conservative treatment and dialysis, the mean nocturnal GH levels were 16 and 25 mU/l, respectively, compared with 8 mU/I in transplanted patients. The number of GH peaks was not affected. A significant correlation between mean peak amplitude and height velocity in the 12 months following the GH profile study was found in the transplanted patients only ( r = 0.66, p < O.OOO5). Both the amplitude and number of peaks of LH were significantly reduced in patients on conservative treatment or dialysis compared with transplanted patients. This difference was the same whether bioactive or immunoreactive LH was used in the calculation. However, the ratio of bioactive to immunoreactive LH was decreased in patients on conservative treatment or dialysis. In addition, a significant correlation was found between this ratio and the plasma testosterone level.
DISCUSSION The results show that statural growth and pubertal development are disturbed in children with chronic renal failure. Pubertal growth appears to start about 2.5 years later than that of healthy children, and the intensity of the pubertal growth spurt is significantly reduced, resulting in insufficient height velocity during puberty and a reduction in predicted adult height (5). Sexual maturation is similarly retarded in both sexes. These results are in agreement with those of previously published studies (1, 3, 6-8). The pathophysiological mechanisms for the failure of growth and puberty in chronic renal failure have so far been largely unexplored. The present investigations have shown marked disruption of nocturnal GH and LH pulsatility in patients on conservative treatment and dialysis, and partial restoration of the physiological patterns after transplantation. Plasma GH levels were markedly raised in patients with uraemia, and did not correlate with growth. In contrast, there was a correlation between the mean GH peak amplitude and the height velocity in the 12 months following the GH profile study in transplanted patients, indicating restoration of the normal physiological relationship after transplantation.
91
92
K. Schdrer et al.
Acta Paediatr Scand [Suppl] 366
The physiological pulsatile pattern of LH secretion characteristic of early puberty was blunted or abolished in patients on dialysis or conservative treatment. This was in accord with the results of an earlier study (9). This appeared to be related to the delay in sexual maturation, though further longitudinal studies are needed to confirm such a relationship. After transplantation, when the pulsatile pattern of LH secretion was partially restored, biopotency of the hormone remained suppressed, perhaps by interference with enzymatic processing of the hormone at the gonadotroph level following immunosuppressive therapy. In summary, there is reduced growth in patients with chronic renal failure during puberty. This impairment in pubertal growth may be related to disruption of the normal physiologicdi pulsatile pattern of GH and LH secretion. ACKNOWLEDGEMENTS The members of the Study Group on Pubertal Development in Chronic Renal Failure are: the Hospital for Sick Children (T.M. Barratt, G. Hammill, S. M e r m a n ) and the Royal Free Hospital (R. Trompeter), London, the University Children’s Hospital, Heidelberg (F. Schaefer, K. Scharer. C. Seidel), the University Children‘s Hospital Medical School, Hannover (G. Offner), Istituto G. Gaslini, Genoa (F. Perfumo), UCLA Center for the Health Sciences, Los Angeles (R.N. Fine), Guy’s Hospital, London (L. Rees), the Hospital for Sick Children. Toronto (D. Geary) and the University Children’s Hospital, Cologne (D. Michalk). Reference laboratories: Department of Chemical Pathology. University of Manchester (W.R. Robertson). Institute of Child Health, London (M. Preece, R. Stanhope), Institute of Pharmacology (P. Vecsei) and Department of Endocrinological Gynaecology (1. Gerhardt, K. Klinga). University of Heidelberg.
REFERENCES I . Scharer K, ed. Growth and endocrine changes in children with chronic renal failure. Paediatric and adolescent endocrinology. Vol. 20. Basel: S Karger. 1989. 2. Scharer K, Chantler C , Brunner FP er a/.Combined report on regular dialysis and transplantation of children in Europe, 1975. Proc Eur Dial Transplant Assoc 1976; 13: 59-103. 3. Kleinknecht C, Broyer M, Gagnadoux MF er af. Growth in children with long-term dialysis. A study of 76 patients. Adv Nephrol 1980: 9: 133-63. 1. Scharer K, Gilli G. Growth in children with chronic renal insufficiency. In: Fine RN. Gruskin AB. eds. End-stage renal disease in children. Philadelphia: WB Saunders, 1984: 271-90. 5 . Schaefer F, Gilli G. Scharer K. Pubertal growth and final height in chronic renal failure. In: Scharer K. ed. Growth and endocrine changes in children and adolescents with chronic renal failure. Paediatric and adolescent endocrinology. Vol. 20. Basel: S Karger. 1989: 59-69. 6. Rizzoni G, Broyer M, Brunner FP er al. Combined report on regular dialysis and transplantation in Europe, 1985. EDTA Registration Committee. 1986. 7. Van Diemen-Steenvoorde R. Donckerwolcke RA. Brackel H. Wolff ED. de Jong MCJW. Growth and sexual maturation in children after kidney transplantation. J Pediatr 1987: 110: 351-6. 8. Boineau FG, Lewy JE. Sexual maturation in children with renal insufficiency: response to dialysis and transplantation. In: Fine RN, Gruskin AB, eds. End-stage renal disease in children. Philadelphia: WB Saunders, 1984: 291-5. 9. Schaefer F, Stanhope R, Scheil LH, Schonberg D. Preece MA. Scharer K. Pulsatile hormone secretion in pubertal children with chronic renal failure. Acta endocrinol (Copenh) 1989: 120: 14-19. (K.S.) Department of Paediatric Nephrology University Children’s Hospital 6900 Heidelberg 1 Federal Republic of Germany
1990
SHORT COMMUNICATION
Growth and Development of Children with Chronic Renal Failure K. SCHARER on behalf of the STUDY GROUP ON PUBERTAL DEVELOPMENT IN CHRONIC RENAL FAILURE From the Department of Paediatric Nephrology. Universiry of Heidelberg. Heidelberg, West Germany
ABSTRACT. Schiirer, K. on behalf of the Study Group on Pubertal Development in Chronic Renal Failure. (Department of Paediatric Nephrology, University of Heidelberg, Heidelberg, West Germany). Growth and development of children with chronic renal failure. Acta Paediatr Scand [Suppl] 366: 90, 1990. Preliminary results from an ongoing multicentre study on pubertal growth and sexual maturation in chronic renal failure are presented. Puberty was delayed by approximately 2.5 years in both sexes in children with chronic renal failure. There was also M irreversible decline in height SDS during puberty. The pulsatile secretion of growth hormone (GH) and luteinizing hormone (LH)were disrupted in patients on conservative treatment or dialysis compared with those in patients with renal transplants; the mean nocturnal GH level and the mean GH peak amplitude were increased, while the number of pulses and peak amplitude of LH were decreased. The biopotency of LH, expressed as the ratio of bioactive to immunoreactive LH, was suppressed in patients with renal transplants. Key words: Chronic renal failure, dehyed pubem, growth failure, gmwth hormone secretion, gonadotrophin secretion.
Growth failure is one of the unsolved problems in children with chronic renal insufficiency (1). The scope of the problem was first recognized some 20 years ago, soon after renal transplantation became available as a therapeutic option. A number of studies have shown that the growth failure is not improved by regular dialysis (2, 3). On the contrary, growth retardation tends to progress during dialysis therapy, resulting in a loss of relative height as determined by height SDS. The growth failure becomes even more pronounced during puberty. In comparison with the results of the First Zurich Longitudinal Growth Study, the onset of the pubertal growth spurt is delayed by approximately 2.5 years in children with chronic renal failure, and the intensity of the growth spurt is also significantly reduced (unpublished results). Malnutrition has been postulated as the main factor responsible for the growth retardation, and a number of studies have shown that nutritional supplementation will stimulate growth in children with chronic renal failure (4). However, other causative factors have been indicated, including metabolic acidosis, hyposthenuria, mineral depletion, uraemic bone disease associated with changes in vitamin D metabolism, and deficiencies of insulin-like growth factors, thyroid hormones and gonadal steroids. It is not yet known whether uraemic toxins are involved in the growth failure, or to what extent renal transplantation itself interferes with normal growth. A multicentre study involving eight paediatric nephrology centres was started 2 years ago and is still currently in progress. The aims of this study are to analyse growth and sexual maturation in pubertal patients in various stages of chronic renal failure, and to determine whether chronic renal failure causes changes in the secretion of hormones regulating the hypothalamo-pituitary-gonadal axis. In particular, the physiological pulsatile secretion of growth hormone (GH) has been investigated in order to assess whether a characteristic pattern of GH secretion is associated with chronic renal failure. This report presents preliminary results from the study.
Acta Paediatr &and [Suppl] 366
Growth in chronic renal failure
PATIENTS AND METHODS Patients with chronic renal failure were selected to enter the study if they were older than 10 years, in pubertal stage I or I1 according to Tanner's staging and, in boys, if the testicular volume was less than 4 ml. In children on conservative treatment (n = 32). creatinine clearance had to be less than 25 mllminutell.73 m2. Patients were also included in the study during treatment by haemodialysis or peritoneal dialysis (n = 9). or after transplantation (n = 22). Children receiving erythropoietin or GH treatment or with systematic disorders such as cystinosis, oxalosis and severe malformation syndromes were excluded. Each patient underwent a clinical examination and laboratory tests every 6 months, and an investigation of hormone secretion every I2 months. For determination of GH and luteinizing hormone (LH) levels, blood samples were withdrawn every 15 minutes from 20.00 hours to 07.00 hours. Other plasma hormones. including follicle stimulating hormone (FSH). prolactin, testosterone, dihydrotestosterone (in boys), oestradiol (in girls), adrenal androgens, insulin-like growth factor I and melatonin, were measured at less frequent intervals. Most hormones were measured by radioimmunoassay; bioactive LH was measured using a mouse Leydig cell assay. Sleep was recorded visually, and hormone profiles were analysed using the Cluster and Pulsar peak detection methods.
RESULTS In the 2-year period up to August 1989, 46 boys and 17 girls were entered into the study. These children had a mean chronological age of 12.8 f 2.0 years (f SD) and a mean bone age delay of 2.5 years (mean bone age 10.3 f 1.9 years). Preliminary results from this group of children showed a decline in height SDS during puberty, height SDS being related to bone maturation. Two patterns of spontaneous GH secretion were observed (unpublished results). During dialysis treatment there was a high baseline level of GH with high amplitude peaks, while after renal transplantation the baseline GH level and peak amplitude were much lower. During conservative treatment and dialysis, the mean nocturnal GH levels were 16 and 25 mU/l, respectively, compared with 8 mU/I in transplanted patients. The number of GH peaks was not affected. A significant correlation between mean peak amplitude and height velocity in the 12 months following the GH profile study was found in the transplanted patients only ( r = 0.66, p < O.OOO5). Both the amplitude and number of peaks of LH were significantly reduced in patients on conservative treatment or dialysis compared with transplanted patients. This difference was the same whether bioactive or immunoreactive LH was used in the calculation. However, the ratio of bioactive to immunoreactive LH was decreased in patients on conservative treatment or dialysis. In addition, a significant correlation was found between this ratio and the plasma testosterone level.
DISCUSSION The results show that statural growth and pubertal development are disturbed in children with chronic renal failure. Pubertal growth appears to start about 2.5 years later than that of healthy children, and the intensity of the pubertal growth spurt is significantly reduced, resulting in insufficient height velocity during puberty and a reduction in predicted adult height (5). Sexual maturation is similarly retarded in both sexes. These results are in agreement with those of previously published studies (1, 3, 6-8). The pathophysiological mechanisms for the failure of growth and puberty in chronic renal failure have so far been largely unexplored. The present investigations have shown marked disruption of nocturnal GH and LH pulsatility in patients on conservative treatment and dialysis, and partial restoration of the physiological patterns after transplantation. Plasma GH levels were markedly raised in patients with uraemia, and did not correlate with growth. In contrast, there was a correlation between the mean GH peak amplitude and the height velocity in the 12 months following the GH profile study in transplanted patients, indicating restoration of the normal physiological relationship after transplantation.
91
92
K. Schdrer et al.
Acta Paediatr Scand [Suppl] 366
The physiological pulsatile pattern of LH secretion characteristic of early puberty was blunted or abolished in patients on dialysis or conservative treatment. This was in accord with the results of an earlier study (9). This appeared to be related to the delay in sexual maturation, though further longitudinal studies are needed to confirm such a relationship. After transplantation, when the pulsatile pattern of LH secretion was partially restored, biopotency of the hormone remained suppressed, perhaps by interference with enzymatic processing of the hormone at the gonadotroph level following immunosuppressive therapy. In summary, there is reduced growth in patients with chronic renal failure during puberty. This impairment in pubertal growth may be related to disruption of the normal physiologicdi pulsatile pattern of GH and LH secretion. ACKNOWLEDGEMENTS The members of the Study Group on Pubertal Development in Chronic Renal Failure are: the Hospital for Sick Children (T.M. Barratt, G. Hammill, S. M e r m a n ) and the Royal Free Hospital (R. Trompeter), London, the University Children’s Hospital, Heidelberg (F. Schaefer, K. Scharer. C. Seidel), the University Children‘s Hospital Medical School, Hannover (G. Offner), Istituto G. Gaslini, Genoa (F. Perfumo), UCLA Center for the Health Sciences, Los Angeles (R.N. Fine), Guy’s Hospital, London (L. Rees), the Hospital for Sick Children. Toronto (D. Geary) and the University Children’s Hospital, Cologne (D. Michalk). Reference laboratories: Department of Chemical Pathology. University of Manchester (W.R. Robertson). Institute of Child Health, London (M. Preece, R. Stanhope), Institute of Pharmacology (P. Vecsei) and Department of Endocrinological Gynaecology (1. Gerhardt, K. Klinga). University of Heidelberg.
REFERENCES I . Scharer K, ed. Growth and endocrine changes in children with chronic renal failure. Paediatric and adolescent endocrinology. Vol. 20. Basel: S Karger. 1989. 2. Scharer K, Chantler C , Brunner FP er a/.Combined report on regular dialysis and transplantation of children in Europe, 1975. Proc Eur Dial Transplant Assoc 1976; 13: 59-103. 3. Kleinknecht C, Broyer M, Gagnadoux MF er af. Growth in children with long-term dialysis. A study of 76 patients. Adv Nephrol 1980: 9: 133-63. 1. Scharer K, Gilli G. Growth in children with chronic renal insufficiency. In: Fine RN. Gruskin AB. eds. End-stage renal disease in children. Philadelphia: WB Saunders, 1984: 271-90. 5 . Schaefer F, Gilli G. Scharer K. Pubertal growth and final height in chronic renal failure. In: Scharer K. ed. Growth and endocrine changes in children and adolescents with chronic renal failure. Paediatric and adolescent endocrinology. Vol. 20. Basel: S Karger. 1989: 59-69. 6. Rizzoni G, Broyer M, Brunner FP er al. Combined report on regular dialysis and transplantation in Europe, 1985. EDTA Registration Committee. 1986. 7. Van Diemen-Steenvoorde R. Donckerwolcke RA. Brackel H. Wolff ED. de Jong MCJW. Growth and sexual maturation in children after kidney transplantation. J Pediatr 1987: 110: 351-6. 8. Boineau FG, Lewy JE. Sexual maturation in children with renal insufficiency: response to dialysis and transplantation. In: Fine RN, Gruskin AB, eds. End-stage renal disease in children. Philadelphia: WB Saunders, 1984: 291-5. 9. Schaefer F, Stanhope R, Scheil LH, Schonberg D. Preece MA. Scharer K. Pulsatile hormone secretion in pubertal children with chronic renal failure. Acta endocrinol (Copenh) 1989: 120: 14-19. (K.S.) Department of Paediatric Nephrology University Children’s Hospital 6900 Heidelberg 1 Federal Republic of Germany
